2009 Influenza A (H1N1) virus

Viral upper respiratory tract infection
Most viruses that cause upper respiratory tract infections are not usually associated with fever, especially in adults.
In most cases, testing for viral infections (e.g., culture) is not performed except in cases where the patient is immunocompromised.
Seasonal influenza
Most commonly seen during the winter months.Generally, diarrhoea and vomiting are less commonly seen with seasonal influenza.
Clinically, distinguishing between seasonal and swine influenza is not necessary, except from an infection control or public health standpoint. Reverse transcriptase-PCR distinguishes between the 2 infections based upon positive reactivity with either the human seasonal influenza panel or the swine influenza panel.
Bacterial pneumonia
Secondary bacterial pneumonia is a known complication of influenza infection, although the incidence is unknown. Bacterial pneumonias also occur more frequently in the winter, when seasonal influenza is circulating. Cough is usually productive. Shortness of breath is more prominent.
CXR demonstrates findings ranging from focal infiltrates to diffuse infiltrates to lobar consolidation, depending on severity and aetiology of the bacterial infection. Influenza infections can cause interstitial infiltrates, but lobar consolidation is uncommon, unless a secondary bacterial pneumonia is present.FBC may reveal elevated WBC count.Sputum or blood culture may reveal positive Gram stain.
SARS
Usually a history of travel within 10 days of onset to a location with documented or suspected recent SARS transmission, or a history of close and prolonged contact with a SARS patient.Early symptoms are typically non-specific (e.g., myalgia, malaise, headache) followed by fever. Cough, which is usually non-productive, develops 2 to 7 days after symptom onset. Dyspnoea is a late symptom, as is a watery diarrhoea, which occurs in the second week in up to 25% of patients.
Tests for influenza virus are negative. Reverse transcriptase-PCR is positive for the SARS virus.
Meningitis
May have similar presentation to influenza infection in children. Headache, neck stiffness, and rash are likely to be more prominent.
Tests for influenza virus are negative. CSF analysis may show increased WBC count, elevated protein, a positive Gram stain (in bacterial meningitis). PCR may be positive for viruses other than influenza in viral meningitis.

Aatrocytoma & Optic glioma

Brain metastasis
May or may not have systemic disease and/or known history of cancer.Systemic symptoms include cachexia, respiratory problems, haemoptysis, chest pain, and bone pain.
MRI: typically, more localised lesions that may be multiple, and with proportionally more vasogenic oedema.Chest-abdominal CT scan, bone scan, and PET scan provide evidence of systemic disease.Histology provides a definitive diagnosis.
Brain abscess
May or may not have systemic symptoms such as fever, cachexia, and chills.Risk factors differ and may include pulmonary abnormalities, congenital cyanotic heart disease, bacterial endocarditis, and penetrating head injury.
MRI demonstrates a thinner capsule toward the ventricle, with restricted diffusion of pus and elevated lactate level; may show multiple lesions.Blood tests suggestive of infection: for example, elevated WBC count, elevated erythrocyte sedimentation rate (ESR), and elevated C-reactive protein (CRP), with sensitivity 90% and specificity 77%. [31]Biopsy or aspiration provides the definite diagnosis, demonstrating pus (inflammatory cells), no tumour cells, and a positive culture of bacterial agent or fungus.
Multiple sclerosis
Typically presents in women aged 20 to 40 years, with acute neurological symptoms that wax and wane (dissemination in space and time): for example, optic neuritis, transverse myelitis (spinal cord symptoms), and focal neurological symptoms.
MRI shows multiple lesions in the periventricular white matter; may or may not enhance.CSF shows oligoclonal bands.Histology provides the definitive diagnosis, demonstrating demyelinating lesions, inflammatory cells, and absence of tumour cells, but usually is not necessary.
Necrosis
Known brain tumour treated with radiotherapy in the past.May present with progressive neurological symptoms or no symptoms at all.
PET scan is cold.Histology provides definitive diagnosis (no tumour cells and extensive necrosis).
Acute stroke
Acute onset of neurological symptoms.Often in older patients with cardiovascular risk factors.Rarely present with seizures (3% to 5% only).
MRI shows typical vasculature distribution and restricted diffusion.
Encephalitis
Systemic symptoms present (fever and cachexia).
CSF shows leukocytosis, Herpes simplex virus (HSV) antibodies, and/or RBCs.EEG is characteristic with periodic lateralising epileptiform discharges.CT or MRI shows oedematous temporal lobes and haemorrhagic transformation.Brain biopsy is definitive with virus isolation.
Oligodendroglioma
No specific difference in clinical presentation except that oligodendrogliomas are more prone to present with seizures.
CT scan demonstrates calcification in 90% of cases.Cortical location on MRI.Histology provides definitive diagnosis with classic fried egg cytoplasm and chicken wire vasculature.
Dysembryoplastic neuroepithial tumour
Typically occurs in patients <20 years of age and presents with chronic seizure disorder.
MRI demonstrates a cortical lesion with distinct margins.CT may show deformity over the calvaria.Histopathology provides definitive diagnosis.
Ganglioglioma
Presents in the first 2 or 3 decades of life with seizure disorder.
MRI commonly demonstrates medial temporal lobe lesion with cystic components and/or calcifications.Histology is definitive with characteristic cell types: ganglion and glial cells.

Abdominal aortic aneurysm

Diverticulitis
Obstipation; abdominal pain is more common and typically localises to the left lower quadrant.No pulsatile abdominal mass on clinical examination. Instead, abdominal or perirectal 'fullness' may be appreciated. Fever is possible. [54]
Stool guaiac testing may be trace positive.Leukocytosis may be present.CT scan will demonstrate a normal-calibre aorta and possibly diverticula, inflammation of the pericolic fat or other tissues, bowel-wall thickness >4 mm, or a peridiverticular abscess. [54]
Renal colic
Severe abdominal pain that starts in the flank and radiates anteriorly to the groin.Associated with nausea, emesis, haematuria, dysuria, and urinary frequency or urgency. [55]
Urinalysis positive for blood and may demonstrate crystals and/or evidence of infection.Ultrasound and CT scan will demonstrate a normal-calibre aorta and possibly ureteral or renal stones. [55]
Irritable bowel syndrome (IBS)
Intermittent abdominal discomfort with flares lasting 2 to 4 days.Associated symptoms may include bloating, stool frequency, and abnormal defecation.Women aged 20 to 40 years are affected more often than men.On examination, most patients appear anxious, although general examination is usually normal. There may be poorly localised abdominal tenderness to palpation. [56]
Imaging modalities are often inconclusive, but will demonstrate a normal-calibre aorta.
Inflammatory bowel disease
Abdominal pain is often 'crampy' and left-sided. Patients typically suffer from diarrhoea (bloody and non-bloody), urgency of defecation, and tenesmus.Extra-intestinal manifestations are common in Crohn's disease.Abdominal examination may demonstrate abnormal bowel sounds, detection of an abdominal mass, and pain on palpation. Mucocutaneous lesions may be visible. Peri-anal fistulae, fissures, or abscesses may be present on rectal examination. [57]
Anaemia is common.Radiographical imaging (i.e., ultrasound or CT scan) will demonstrate a normal-calibre aorta.Endoscopic evaluation with biopsy shows typical lesions of ulcerative colitis or Crohn's disease. [57]
Appendicitis
Pain is typically periumbilical with localisation to the right lower quadrant.Associated nausea, emesis, and anorexia are common.Patients are classically febrile with tenderness in the right lower quadrant or rebound tenderness on abdominal examination.
Leukocytosis and sterile pyuria on urinalysis is common.Imaging with ultrasound or CT scan will demonstrate a normal-calibre aorta with an inflamed appendix or evidence of perforation.
Ovarian torsion
Women suffer sudden, continuous, non-specific pain in the lower abdomen; nausea and emesis are common. Patients may demonstrate fever on clinical examination and an adnexal mass may be palpable. [58]
Leukocytosis may be present. Ultrasound will demonstrate a normal calibre aorta and possible reduced or absence of adnexal vascular flow. [58]
GI haemorrhage
Patients presenting with haemorrhagic shock may mimic aortic rupture. A history of previous GI bleed, haematemesis, melaena, or bright red blood per rectum is common.Historical risk factors for GI malignancy or peptic ulcer disease may be elicited.On rectal examination gross blood may be visible or coffee ground haematemesis may be returned with nasogastric tube placement.
Stool is likely to be guaiac positive.Endoscopic evaluation may demonstrate the luminal bleeding source along with mucosal ulcerations, polyps, or tumour.Radiographical imaging with ultrasound or CT scan will demonstrate a normal calibre aorta.
Splanchnic artery aneurysms/acute occlusion
Acute embolic or thrombotic occlusion of the splanchnic vessels results in a marked disparity between acute excruciating mid-abdominal pain and a paucity of early physical findings.Patients typically suffer unremitting, intense mid-abdominal pain with nausea and vomiting that might be accompanied by explosive diarrhoea.Most splanchnic artery aneurysms are asymptomatic until rupture. [59]
Leukocytosis, haemoconcentration, and systemic acidosis are common with acute splanchnic vessel occlusion. Elevated levels of serum amylase, inorganic phosphorous, creatinine phosphokinase, and alkaline phosphatase may accompany frank bowel infarction.Angiography is diagnostic and potentially therapeutic in the case of vascular occlusion.Ultrasound and CT scan will demonstrate a normal-calibre aorta and will diagnose any splanchnic artery aneurysms. [59]

Abetalipoproteinaemia

Crohn's disease
Both patient groups suffer from a chronic course; however, diarrhoea occurs with painful bouts in Crohn's disease, whereas abetalipoproteinaemia is painless. Additionally, patients with Crohn's disease rarely present in infancy.
Blood tests showing low microsomal triglyceride transfer protein (MTTP) and absent or low apolipoprotein B (apo B) aid in differentiation. Colonoscopy and a barium meal and follow-through with X-ray are helpful to identify Crohn's disease.
Ulcerative colitis
Both patient groups suffer from a chronic course; however, diarrhoea occurs with painful bouts in ulcerative colitis, whereas abetalipoproteinaemia is painless. Additionally, patients with ulcerative colitis disease rarely present in infancy.
Blood tests showing low MTTP and absent or low apo B aid in differentiation. Endoscopy with biopsy helps differentiate ulcerative colitis.
Viral gastroenteritis
Abetalipoproteinaemia is chronic while viral gastroenteritis is time-limited and occurs with fever.
Blood tests showing low MTTP and absent or low apo B aid in differentiation.
Child abuse
Child abuse is generally manifested by failure to thrive without steatorrhoea or ocular signs and symptoms.
Blood tests showing low MTTP and absent or low apo B aid in differentiating abetalipoproteinaemia.In child abuse, radiological studies may show multiple healed fractures or suspicious spiral fractures.
Homozygotic hypobetalipoproteinaemia
The heterozygous parent of a patient with homozygotic hypobetalipoproteinaemia typically has a reduced serum cholesterol concentration but is otherwise generally normal with no signs or symptoms. [1]
In homozygotic hypobetalipoproteinaemia, the patient's parents will have low plasma LDL and low apoprotein B levels. [1]

Absence seizures

Daydreaming
More likely to occur only during quiet, non-stimulating activities such as watching TV. No history of activity cessation. No unusual episodes induced by hyperventilation.
EEG will be normal.
Attention deficit hyperactivity disorder (ADHD)
More likely to occur only during quiet, non-stimulating activities such as watching TV. No history of activity cessation. No unusual episodes induced by hyperventilation.
EEG will be normal. A variety of neuropsychological tests can help with formalising diagnosis.
Complex partial epilepsy of frontal or temporal lobe origin
Patients more likely to have eye deviation, facial twitching, or other localising component at onset of seizure. Seizures typically last at least 30 seconds. There may be a preceding aura and a postictal state.
EEG will be normal, asymmetric, or show focal epileptiform abnormality.
Psychogenic unresponsiveness/non-epileptic event
Careful history will likely elicit characteristics of the unusual episode that are atypical for any kind of seizure. In some instances a social history may reveal a stressor that is precipitating these events.
Routine EEG will be normal. It is often necessary to do prolonged video EEG monitoring to completely characterise the event and establish that there is no ictal electrographical abnormality.

Acanthosis nigricans

Epidermal nevus
Usually presents in children on the neck, torso, and extremities rather than the flexural and intertriginous areas typically involved by AN. [6] Lesions may be linear or verrucous in appearance.
Skin biopsy shows variable degrees of epidermal hyperplasia, papillomatosis, and inflammation.Some cases may show features indistinguishable from AN, but there is typically less papillomatosis and more inflammation than seen in AN. [6]As some authors consider AN a type of epidermal nevus, the distinction may be academic in some cases. [4] [6]
Dowling-Degos disease (reticular pigmented flexural anomaly)
Lesions with reticulated pattern in flexural areas. [25]Lesions do not appear thickened and velvety-appearing as those of AN.Patients may also have lesions on the hands and feet and palmoplantar pitting. [26]
Skin biopsy shows filiform downgrowths of epidermis with pigmented rete ridges and occasional pseudohorn cysts, resembling seborrhoeic keratosis.Papillomatosis and hyperkeratosis resembling AN are not seen. [26]
Confluent and reticulated papillomatosis (of Gougerot and Carteaud)
Red/brown verrucous-appearing papules with central confluence and peripheral reticulate pattern.Typically presents on the central chest or back, not flexural areas as in AN. [27]
Skin biopsy shows epidermal acanthosis and low papillomatosis (less prominent than AN), and may show basilar pigmentation. [27]There may also be mild telangiectasia and beading of elastic fibres, findings not seen in AN.
Seborrhoeic keratosis
Common lesions of adults that usually present as one or a few well-defined pigmented papules on the chest, back, and face.Most lesions are small, although rare plaque-like lesions have been reported on the buttocks or thighs.
Skin biopsy shows epidermal acanthosis with pseudohorn cysts and variable papillomatosis. The lesions are usually more endophytic than AN, and the papillomatosis is more irregular.There is often inflammation and associated squamous differentiation with eddies, findings not seen in AN.
Mycosis fungoides
Long-standing patches and plaques in bathing-trunk distribution, typically not velvety or clinically pigmented. [28]Rare presentation may mimic AN clinically. [29]
Skin biopsy shows epidermotropism by enlarged, atypical lymphocytes, often with nuclear hyperchromasia and hyperconvolutions.Immunohistochemistry shows an increased CD4:CD8 ratio in most cases. Molecular analysis shows clonal T-cell gene re-arrangement. [28]
Lichen simplex chronicus/eczematous dermatitis
Hyperpigmented, lichenified plaques resulting from excessive scratching or rubbing of skin.Often very pruritic.Common sites include posterior neck like AN and extremities.
Clinical features sufficient to distinguish these entities without further investigation.
Ichthyosis hystrix
Generalised hyperkeratosis often with hyperpigmented verrucous surface. [30]This can resemble familial, benign AN that may have generalised, hyperkeratotic, ichthyosiform plaques and be inherited in an autosomal-dominant pattern. [2] [31]
On skin biopsy, ichthyosis hystrix may have a pattern of epidermolytic hyperkeratosis or more non-specific findings of hyperkeratosis, hypergranulosis, acanthosis, and papillomatosis. [30]
Pemphigus
Resolving pemphigus vulgaris or pemphigus foliaceus may have a papillomatous, hyperpigmented appearance, which clinically and histologically resembles AN. [32] [33]
Pemphigus patients have auto-antibodies that can be detected in the blood or by direct immunofluorescence of skin lesions. [33]
Tinea corporis
May clinically resemble AN, especially if component of post-inflammatory hyperpigmentation is present.
There should be evidence of dermatophyte on scraping for KOH or Periodic Acid-Schiff staining on histology.

Achalasia

Oesophageal carcinoma
Dysphagia is mainly for solids, although difficulty in swallowing liquids develops with advanced disease.Weight loss may be severe.
Barium swallow and endoscopy will show oesophageal obstruction by the tumour.
Reflux oesophagitis
Can give rise to dysphagia through inflammatory swelling or a fibrotic peptic stricture, or even in the absence of endoscopic abnormalities.The patient will usually also report heartburn and/or regurgitation in addition to dysphagia.
Endoscopy will show reflux oesophagitis, with or without a peptic stricture. A hiatus hernia may be present below the stricture.Barium swallow has low sensitivity for oesophagitis but will show up strictures and hiatus hernias. Gastro-oesophageal reflux will be demonstrated.Lower oesophageal pH studies will demonstrate pathological gastro-oesophageal reflux.
Connective tissue disorders (e.g., systemic sclerosis)
Muscle and joint pain, Raynaud's phenomenon, skin changes (e.g., rash, skin swelling or thickening).
Antinuclear antibodies, rheumatoid factor, creatine kinase, and ESR are useful initial screening tests for connective tissue pathology.
Oesophageal spasm
Chest pain is often more prominent than dysphagia, which tends to be intermittent.
Manometry shows high-amplitude oesophageal contractions rather than the aperistalsis usually seen in achalasia.
Eosinophilic oesophagitis
Presents with intermittent dysphagia, often in young men with history of atopy.
Oesophageal biopsy shows eosinophilic infiltration (>15 eosinophils per high-power field).
Pseudoachalasia (or secondary achalasia)
Underlying malignancy that mimics idiopathic achalasia.Patients tend to be older, duration of symptoms shorter, [17] and weight loss greater and more rapid.Dysphagia is clinically indistinguishable.
Gastroscopic biopsy of gastro-oesophageal junction and cardia may demonstrate malignancy.Findings at endoscopy, barium swallow, and manometry may be indistinguishable from achalasia.
Chagas' disease
Endemic to Latin America; multiple-organ involvement probably causing atonic colon, myocarditis, and Romana sign; swelling of the eyelids in acute disease.
Microscopic examination of fresh blood showing presence of Trypanosoma cruzi.PCR for precise identification of trypanosome subtype.Giemsa staining of thick and thin blood films detects parasite.

Achlorhydria

Anti-secretory drug-induced hypochlorhydria and hypergastrinaemia
Although rare, proton-pump inhibitor-induced hypochlorhydria can interfere with the absorption of iron and cobalamin. [68] [70] [71] There are reports of increased bone fractures in patients on long-term proton-pump inhibitors, possibly due to cobalamin, calcium, and/or vitamin D malabsorption. [10] [11] [12] [98]Proton-pump inhibitors selectively inhibit parietal cell H+/K+ ATPase, the proton pump responsible for the final step in acid secretion, and thereby inhibit both basal and stimulated gastric acid secretion. [1] [36] Because their half-lives are about 1 hour and new pumps are continually being made, patients are not achlorhydric, and median 24-hour gastric pH is about 4.0 to 5.0. [34] [35] As a result of hypochlorhydria, gastrin levels are elevated in about 20% of patients, usually less than 2- to 4-fold. However, about 5% of patients may have gastrin levels exceeding 400 picograms/mL. [64] [65] [66]
The simplest way to differentiate anti-secretory drug-induced hypochlorhydria and/or hypergastrinaemia as well as nutrient malabsorption is to discontinue the drug and observe return to normal of serum gastrin, iron, cobalamin, and 25-hydroxyvitamin D.

Acne rosacea

Seborrhoeic dermatitis
Yellow greasy scales on an erythematous base in a seborrhoeic distribution (peri-orificial and on the scalp). Usually scaly.
Clinical differentiation usually suffices.
Contact dermatitis
Vesicles and pseudo-vesicles.
Patch testing will be positive for specific contact allergens.
SLE
Discoid or malar 'butterfly' distribution; rash often associated with photo-sensitivity; oral ulcers; serositis; renal disorder; neurological disorder; haematological disorder; immunological disorder.
ANA positive; hypo-complementaemia; anti-Ro antibodies positive; anti-double-stranded DNA antibodies positive.
Dermatomyositis
Peri-orbital confluent macular violaceous (heliotrope) erythema, Gottron's papules, pruritus and/or burning of the skin, sensitivity to sunlight, muscle weakness, pain, and tenderness.
Positive ANA (speckled and nucleolar immunofluorescence patter); anti-Jo-1 antibody positive.
Photodermatitis
General erythema in photo-distribution.
Clinical differentiation usually suffices.
Carcinoid syndrome
Flushing, diarrhoea, bronchoconstriction; right-sided cardiac valve disease.
Elevated 24-hour urinary 5-HIAA levels.
Mastocytosis
Flushing, pruritus, urtication, abdominal pain, nausea or vomiting, diarrhoea, musculoskeletal pain, headache, vascular instability, neuropsychiatric difficulties.
Presence of dense infiltrate of mast cells on tissue biopsy. [9]
Polycythaemia vera
History of bleeding or thrombosis. Other common clinical features include headache, generalised weakness, splenomegaly, excessive pruritus, plethora, or erythromelalgia (tenderness or painful burning and/or redness of fingers, palms, heels, or toes).
Presence of elevated haemoglobin and normal arterial oxygen.
Sarcoidosis
Translucent yellow-red papules that appear as an 'apple jelly' when compressed with a glass slide (diascopy).
Characteristic granulomatous findings on biopsy of sarcoidal skin lesions, sometimes non-specific.
Dermatitis due to long-term use of corticosteroids
Generalised redness with atrophy of skin; possible striae.
Clinical differentiation usually suffices.
Acne vulgaris
Typically affects younger patients and begins with puberty. Presence of whiteheads (closed comedones) and blackheads (open comedones). Lack of flushing and lack of significant erythema.
Clinical differentiation usually suffices.
Allergic conjunctivitis
Presence of a watery or ropy mucoid discharge. Itching is the primary complaint. It is most commonly seasonal and often associated with a history of atopic dermatitis, hay fever, and asthma.
Clinical differentiation usually suffices.
Inflammatory keratosis pilaris
Most often limited to the extremities and presents with more distinct papules (as opposed to papules on a background of erythema, as seen in rosacea). A more inflammatory form of keratosis pilaris can sometimes be confused with rosacea. While keratosis pilaris is extremely common, making a clinical distinction between rosacea and keratosis pilaris is not often difficult.
Clinical differentiation usually suffices.
Demodex folliculitis
Demodex folliculitis on the face and trunk presents with a clinical picture that can be almost identical to rosacea. Condition will respond to treatment with oral ivermectin or topical permethrin, which would have no effect on rosacea.
Skin scraping will demonstrate numerous demodex mites.

Acne vulgaris

Acne keloidalis nuchae
Most often seen in black patients; lesions are typically localised to the posterior neck. They begin as papules and pustules and may progress to confluent keloids. [25]
Clinical differentiation usually suffices.
Acneiform eruptions
Possible aetiologies to consider include oral medicines, topical corticosteroids, contrast dye, testosterone, and cosmetic products.Clinical clues include the abrupt onset of lesions within days of exposure, widespread involvement, atypical locations, atypical age, and improvement with cessation of medicine or exposure.
Clinical diagnosis usually suffices.
Chloracne
Comedones, pustules, and cysts are most commonly found behind the ears and in the axillae and groin.Consider exposure to halogenated aromatic hydrocarbons (e.g., chlorinated dioxins and dibenzofurans). Patient may have systemic complications such as ophthalmic, neuropathic, hepatic, and lipoprotein abnormalities. [26]
Clinical differentiation usually suffices.Consider laboratory tests such as liver enzymes and lipid panel.
Favre-Racouchot syndrome
Multiple open and closed comedones on the peri-orbital and malar areas, usually on older people with significant chronic sun exposure. Typically non-inflammatory.
Clinical differentiation usually suffices.Skin biopsy shows increased elastic tissue with thickened, tortuous fibres in the upper and mid-dermis. [27]
Folliculitis (non-gram-negative)
Common condition that manifests as erythematous papules and pustules, which are follicularly based.As opposed to acne, folliculitis often affects the trunk and extremities.
Clinical differentiation usually suffices.Pustular lesions that do not respond to typical acne antibiotics may be cultured.
Gram-negative folliculitis
Occurs in patients with acne treated with long-term antibiotics who subsequently develop pustules or nodules on the anterior nares, which then spreads. Can also occur in people after hot tub immersion, as well as in HIV patients.
Lesions may be cultured to isolate the gram-negative bacteria if acneiform lesions do not respond to typical antibiotic regimen.
Lupus miliaris disseminatus faciei
Firm yellowish-brown or red smooth papules peri-orbitally and characteristically on the eyelid skin. [28]
Diascopy reveals yellowish-brown lesions. Skin biopsy reveals caseating epithelioid cell granulomas.
Milia
White keratinaceous cysts that are found on the face, particularly on the eyelids. Lesions are fixed and persistent.
Skin biopsy shows small cysts derived from the infundibulum of the vellus hair.
Peri-oral dermatitis
Common peri-oral eruption of papules and pustules on an erythematous and/or scaling base, often the result of topical corticosteroid use. Localised symmetrically around the mouth, with a clear zone around the vermilion border. [29]
Clinical differentiation usually suffices.
Pyoderma faciale
Rapid onset of reddish or cyanotic erythema with abscesses, cysts, and occasionally sinus tracts. No comedones and no involvement of back or chest. [30]
Skin biopsy shows a grenz zone and mixed inflammatory infiltrate in the upper and mid-dermis, with extravasation of RBCs and haemosiderin deposition.
Rosacea
Typically affects older people than acne vulgaris, most often women aged 30 to 50 years.Various forms, but classically presents with background erythema and telangiectasias, and inflammatory papules and pustules occasionally superimposed.Environmental factors often act as triggers.
Clinical differentiation usually suffices.
Syringoma
Non-inflammatory small papules that occur primarily on the eyelids and upper cheeks, usually multiple.Disproportionately more prevalent in Japanese women.
Skin biopsy shows a dense fibrous stroma with dilated cystic spaces that have small comma-like tails resembling tadpoles.
Adenoma sebaceum (angiofibromas)
Small, translucent, waxy papules distributed symmetrically over the central cheek, nose, and forehead.Multiple lesions associated with tuberous sclerosis. [31]
Skin biopsy shows dermal fibrosis and vascular proliferation and dilation.

Acoustic neuroma

Meningioma
Hearing loss is a less prominent symptom.
CT and MRI imaging findings show a large angle between the tumour and dura not centred over the internal acoustic meatus. Often has a dual tail.Also, imaging displays bone hyperostosis, no internal acoustic meatus enlargement, and no or less extension into the internal acoustic meatus.
Epidermoid
Hearing loss is a less prominent symptom.
MRI imaging shows non-enhancing T1- and T2-weighted images.
Facial nerve schwannoma
Facial weakness is prominent and occurs early.Sometimes associated with neurofibromatosis.
CT and MRI imaging results are similar to acoustic neuroma; however, enhancement extends into the geniculate ganglion of the facial nerve and facial canal.
Trigeminal schwannoma
Clinically associated with more prominent facial numbness.Hearing loss is also less prominent.
CT and MRI imaging displays a dumbbell-shaped mass over the petrous apex affecting Meckel's cave.The trigeminal nerve enhancement extends proximal to the tumour and does not extend into the internal acoustic meatus.

Acquired torticollis

Arthritis of cervical spine
Pain with passive neck movement, or crepitus, may occur with or without acquired torticollis.
Degenerative skeletal changes on MRI of the neck.
Neck mass
Visible or palpable mass, limited passive ROM.
Mass visualised on neck MRI.
Cerebral mass, lesion or infarct
Neurological abnormalities (e.g., hemiparesis, asymmetrical reflexes, cognitive and/or personality changes).
Mass lesion or infarct visualised on brain MRI.
Posterior fossa mass
Symptoms provoked by neck extension, prominent headache, nausea and vomiting, dizziness.
Posterior fossa mass visualised on brain MRI.
Retropharyngeal abscess
Systemic signs of infection, dysphagia.
Enhancing mass on neck MRI.
Parkinsonian syndromes
Bradykinesia and rigidity beyond neck area, tremor, gait abnormality, postural instability, autonomic instability.
Differentiated by clinical examination findings only.
Huntington's disease
Hyper-kinetic movements involving other body parts and/or cognitive and behavioural symptoms.Suggestive FHx.
Detection of 36 or more cysteine/arginine/guanine repeats in the Huntington's disease gene.
Tic disorder
Abnormal neck movements accompanied by frequent tics such as blinking, ocular deviations, or sniffing.
Differentiated by clinical history and exam findings only. Tics are usually preceeded by premonitory urge followed by release of tension with performance.
Dopa-responsive dystonia
Childhood onset.Responds therapeutically to a trial of levodopa.
Differentiated by clinical examination findings only.
Trochlear nerve palsy
Extra-ocular movements limited.Diplopia corrected by abnormal head posture.
Differentiated by clinical history and exam findings only.
Primary torsion dystonia (DYT-1)
Onset before fourth decade.Generalised dystonia.
Presence of DYT-1 gene mutation.
Wilson's disease
Accompanying neuropsychiatric abnormalities.Kayser-Fleischer rings present on slit-lamp examination.
Low serum ceruloplasmin, increased urinary copper excretion, mutation in ATP7B gene.
Psychogenic dystonia
Suggestive symptoms include previous somatisation, abrupt onset, secondary gain and absence of sensory trick.Psychogenic dystonia is rare and should be diagnosed with caution.
Differentiated by clinical examination findings only.

Acromegaly

acromegaloidism or pseudo-acromegaly
Clinical features do not reliably differentiate the condition from acromegaly.
Insulin-like growth factor 1 normal.Random GH below 0.4 microgram/L (<0.4 nanograms/mL).Oral glucose tolerance test (OGTT) nadir GH below 1 microgram/L (<1 nanogram/mL).Fasting blood sugar and/ or OGTT glucose levels may be markedly elevated.

Actinic keratosis

Squamous cell carcinoma (SCC) in situ (Bowen's disease)
Lesions similar to AKs, with similar distribution, but usually solitary. Can become larger, indurated, inflamed, redder, ulcerated, and bleeding.Can occur on covered areas including mucous membranes and genital areas.
Skin biopsy shows an intra-epithelial SCC in situ.Atypical (anaplastic) keratinocytes are present throughout the entire epidermis, including follicular infundibulum.There is a thick parakeratotic horny layer and large dyskeratotic cells. Basement membrane is intact. [3] [4] [12] [11] [49] [48]
Invasive SCC
Lesions begin similarly to AKs or Bowen's disease.Generally a larger red ulcer with a thick border and a granular base.Has the potential to metastasise.
Skin biopsy shows atypical (anaplastic) keratinocytes throughout entire epidermis, invading dermis.Differentiated tumours have fewer atypical cells and more keratinisation (e.g., horn pearls) than undifferentiated.Anti-cytokeratin 13 antibodies distinguish them from other tumours. [3] [4] [12] [11] [49] [48]
Keratoacanthoma
Very early and late lesions are most likely to resemble AKs. [3] [49] Clinically similar to well-differentiated SCC.Dome-shaped lesion, colour of normal skin or red, with a central keratinous crater.Grows rapidly but tends to regress spontaneously.
Early lesion skin biopsy shows ill-defined epidermal invaginations into dermis, containing keratinocytes with little nuclear atypia and mitotic figures, and some dyskeratotic cells.Developed lesion biopsy shows a centred crater filled with keratin, surrounded by lip-shaped epidermal extensions. Many horn pearls are seen. [3] [49]
Basal cell carcinoma
A small, smooth nodule with a translucent pearly border, and telangiectasia seen through the surface.Most are localised on the face; less likely to be found on the trunk.Hyperpigmented lesions sometimes occur, resembling malignant melanoma and other melanocytic lesions. [49]
Skin biopsy shows nodular masses of large basaloid cells with large nucleus and little cytoplasm, peripheral palisading that extends into dermis.Cystic spaces present between tumour cells and stroma. [49]
Seborrhoeic keratosis
Elevated, well-defined velvety plaques, localised on either sun-exposed or covered areas.Most have a verrucous surface, and may have keratotic plugs and irregular crypts.Lesions can grow and become thicker and more pigmented
Dermoscopy reveals yellow-white globular structures corresponding with keratin-filled cysts (horny pseudocysts), pseudofollicular openings (yellow-brown crypts), and absent network. [50] [51]
Localised discoid lupus erythematosus (DLE)
Well-defined, erythematous, round papules and plaques, some infiltration, with thick scaling. As DLE plaques enlarge, a central area of atrophy and hypopigmentation develops with a hyperpigmented periphery. [52] [53]In general, lesions localised anywhere above the neck, in the same distribution as AKs.
Skin biopsy shows perivascular mononuclear inflammation, interface inflammation with basal keratinocytic vacuolisation, thickening of basement membranes, telangiectasia, epidermal atrophy, and acanthosis. [49] [54] [55]
Hypertrophic lupus erythematosus
A variant of DLE with verrucous hyperkeratotic and crusting lesions.
Skin biopsy shows pseudocarcinomatous epithelial hyperplasia, with a band-like dermal-epidermal junction and perivascular lymphocytic infiltrate, and colloid bodies in the papillary dermis. [56] [57]Very often resembles SCC histologically. [52] [56]
Sub-acute cutaneous lupus erythematosus
Non-scarring, non-atrophic papulosquamous or annular polycyclic lesions, morphologically intermediate between DLE and SLE. [53] Twenty percent of these patients have concomitant DLE lesions [58] [59] and 50% fulfil criteria for SLE. [49] [58] [60]Localised on the trunk and extensor aspects of the upper extremities rather than face and neck.Unlike AKs, more likely to occur in women.Up to 70% of patients have extracutaneous manifestations including mild arthralgias. [49] [58]
Skin biopsy shows interface lichenoid dermatitis, basal keratinocytic vacuolisation, suprabasilar clefts and vesicles, lymphocytic exocytosis, colloid bodies in lower epidermis and papillary dermis, marked edema, and focal erythrocyte extravasation.Associated with HLA-DR2 and HLA-DR3. Seventy percent are anti-Ro (SS-A)-positive. [49] [58] [61]
Psoriasis
Well-defined pink to erythematous confluent papules and plaques covered with silvery scales, revealing small bleeding points on scraping (Auspitz sign).An eruptive form with small plaques (guttate psoriasis) may occur after acute group A beta-hemolytic streptococcal throat infections.May be nail involvement including pitting, erythrodermia, arthritis, and pustular lesions. [49] [62] [63]
Skin biopsy shows acanthosis, focal vacuolisation, and disappearance of granular cells with overlying parakeratosis, oedema, and capillary dilation in elongated papillary dermis.Lymphocytes infiltrate perivascular area. Neutrophils in parakeratotic areas form Munro micro-abscesses, and neutrophils in spinous layer form pustules of Kogoj. [49] [63]
Disseminated superficial actinic porokeratosis
Lesions are localised mostly in the extensor surfaces of the extremities and can occur in the face.Small, superficial, skin-coloured, erythematous or pigmented plaques surrounded by a narrow, elevated hyperkeratotic ridge. [49]
Clinical findings should suffice to distinguish from AKs. Skin biopsy shows characteristic deep invaginations of keratin into the epidermis with central parakeratosis (cornoid lamella). [49]
Large cell acanthoma
A small hyperkeratotic, well-defined plaque that develops in sun-exposed areas.Resembles AKs, in the type of lesion, the pattern of distribution (e.g., head and extremities), and size of the lesions (<1 cm).It has been related to lentigo senilis (solar lentigo), [64] [65] stucco keratosis, [66] lichen planus-like AK, [67] and Bowen's disease. [68]
Skin biopsy shows large keratinocytes with large nuclei arranged in a disorganised pattern. [49]Nuclear dysplasia may be present and mitoses are infrequent. Acanthosis, hypergranulosis, and orthohyperkeratosis may also be present.
Solar lentigo
Well-defined, irregular, very small hyperpigmented macules localised over sun-exposed areas.
Skin biopsy shows elongated, fused rete ridges, with small bud-like extensions. Thin epidermis over the rete ridges. Low epidermis with hyperpigmented basaloid cells and strong DOPA-positive dendritic melanocytes.Dermoscopy: discrete regular network, uniform pigmented background, absent brown globules. [51]
Warts
Well-defined, usually round, firm, papillomatous papules associated with human papilloma virus (HPV) infection.Located on dorsal aspects of the fingers and hands, where they can resemble hyperkeratotic AKs.The filiform variant is mostly seen on the face and scalp of older children rather than in older people. [49]
Skin biopsy shows a thick epidermis with papillomatosis, and hyperkeratosis. Elongated rete ridges, focal cell vacuolisation (koilocytotic cells), and parakeratotic cells.PCR HPV-DNA amplification may detect viral antigens including HPV common antigen.In-situ hybridisation may identify viral genomic material. [49]
Lichen planus
Few or multiple violaceous well-defined papules with fine white lines on the surface.Lichen planus-like (lichenoid) AK lesions morphologically resemble lichen planus, and tend to be localised on sun-exposed areas.In addition, lichen planus can be frequently found in mucous membranes, genitals, and nails.
Skin biopsy reveals characteristic hyperkeratotic epidermis, irregular acanthosis, focal thickening of the granular layer, liquefaction of basement membrane, and band-like lymphocytic infiltrate in the upper dermis. [49]

Actinomycosis

Abdominal abscess
Features of sepsis or an acute abdomen are generally prominent, although the early symptoms of abdominal actinomycosis may be similar to an abdominal abscess.
Histology and culture for actinomycetes are negative.Blood or site cultures identify causative organism.
Ovarian or oviductal tumour
Symptoms may be similar to pelvic actinomycosis. However, the association of a pelvic mass in an IUD user strongly suggests the diagnosis of actinomycosis. Leukorrhoea is less likely to be present.
Histopathology shows malignancy. Histology and culture for actinomycetes are negative.
Appendicitis
Features of an acute abdomen are generally prominent, but symptoms may be otherwise similar to abdominal actinomycosis.
Histology and culture for actinomycetes are negative.
Blastomycosis
Lung blastomycosis may spread to the skin, but otherwise symptoms may be similar to pulmonary actinomycosis.
Sputum smear and culture using KOH preparations or specific stains can confirm diagnosis. Histology and culture for actinomycetes are negative.
Brain abscess
Clinical features may be similar to actinomycosis of the CNS.
Blood cultures may be positive with a bacterial abscess. Histology and culture for actinomycetes are negative.
Colon cancer
Clinical features of abdominal actinomycosis may mimic colon cancer.
Histology shows malignant tissue. Histology and culture for actinomycetes are negative.
Gastric adenocarcinoma
Symptoms of abdominal actinomycosis may mimic gastric adenocarcinoma.
Histology shows malignant tissue. Histology and culture for actinomycetes are negative.
Crohn's disease
Clinical features may be indistinguishable from abdominal actinomycosis.
Colonoscopy shows skip lesions. Biopsy shows characteristic changes. Histology and culture for actinomycetes are negative.
Ulcerative colitis
Clinical features may be indistinguishable from abdominal actinomycosis.
Biopsies show continuous distal disease with characteristic changes and an absence of granulomata. Histology and culture for actinomycetes are negative.
Diverticulitis
Clinical features may be indistinguishable from abdominal actinomycosis.
Colonoscopy or sigmoidoscopy may show diverticula. Histology and culture for actinomycetes are negative.
Liver abscess
Clinical features may be indistinguishable from abdominal actinomycosis.
Blood cultures may be positive in pyogenic liver abscess. Histology and culture on aspirated fluid is negative for actinomycetes. Ultrasound demonstrates a variably echoic lesion.
Lung abscess
Clinical features may be indistinguishable from thoracic actinomycosis.
Very high WBC count is common. Sputum Gram stain and culture may reveal a causative pathogen. Histology and culture for actinomycetes are negative.
Lung cancer
Clinical features may be indistinguishable from thoracic actinomycosis.
Sputum cytology may reveal malignant cells. Biopsy shows malignant cells. Histology and culture for actinomycetes are negative.
Nocardiosis
Clinical features may be indistinguishable from abdominal actinomycosis.
Modified acid-fast staining of biopsy tissue or other samples allows distinction between Nocardia and Actinomyces.
Pelvic inflammatory disease
History of recent sexual contact, recent onset of menses, or a sexually transmitted infection in the partner, as well as a past history of PID, are common. However, the clinical symptoms of PID may resemble pelvic actinomycosis, and definitive diagnosis requires laparoscopy with biopsy sampling followed by histology.
Culture of vaginal secretions may be positive for a sexually transmitted organism. Endometrial biopsy may show changes of endometritis. Histology and culture for actinomycetes are negative.
Pneumonia (fungal, bacterial, or aspiration)
Clinical features may be indistinguishable from thoracic actinomycosis.
Sputum Gram stain and culture may reveal a causative pathogen. Histology and culture for actinomycetes are negative.CXR may typically show focal changes in bacterial pneumonia, with large pleural effusion, cavitating changes indicating an abscess, or multifocal or interstitial changes.
Pulmonary tuberculosis
Clinical features may be indistinguishable from thoracic actinomycosis.
Sputum smear and culture positive for acid-fast bacilli. Tuberculin skin testing is usually positive. Histology and culture for actinomycetes are negative.
Intestinal tuberculosis
Clinical features may be indistinguishable from abdominal actinomycosis.
Histology and culture of infected tissue are positive for acid-fast bacilli. Tuberculin skin testing is usually positive. Histology and culture for actinomycetes are negative.
Uterine cancer
Clinical features may be indistinguishable from pelvic actinomycosis.
Biopsy tissue at laparoscopy shows malignant tissue. Histology and culture for actinomycetes are negative.
Whipple's disease
Typically presents as an acute GI illness, with fever, diarrhoea, and weight loss, often with features of malabsorption such as steatorrhoea, oedema, fatigue, and lethargy. A severe wasting syndrome with abdominal lymphadenopathy and abdominal pain may develop. Joint problems often occur, and a seronegative migratory arthralgia of the large joints or other forms of arthritis may be the presenting feature. Most patients are anaemic.
Anti-Tropheryma whipplei-positive macrophages, carried out on biopsied tissue, are a diagnostic marker. Polymerase chain reaction testing of duodenal biopsies positive for T whipplei (although carriers may also have positive results).

Acute appendicitis

Acute mesenteric adenitis
Usually presents in children with a recent history of upper respiratory infection.Pain in the abdomen is usually diffuse with tenderness not localised to the right lower quadrant.Guarding may be present, but rigidity is usually absent.Generalised lymphadenopathy may be noted.
There is no specific test to confirm the diagnosis.Relative lymphocytosis in WBC differential counts is suggestive.Negative ultrasound or CT findings help exclude other diagnoses.
Viral gastroenteritis
Common in children; caused by viruses, bacteria, or toxin.Characterised by profuse watery diarrhoea, nausea, and vomiting.Crampy abdominal pain often precedes the diarrhoea, and no localising signs are present.If caused by typhoid fever, intestinal perforation may cause localised abdominal pain and/or generalised and rebound tenderness. In this scenario, associated maculopapular rash, inappropriate bradycardia, and leukopenia will differentiate from appendicitis.
No specific test unless due to typhoid (Salmonella typhi from stool or blood will confirm the diagnosis).
Meckel's diverticulitis
Usually asymptomatic.Only 20% of the patients present with diverticulitis, and 50% of this group are aged <10 years. [40]Clinical presentation of diverticulitis is similar to acute appendicitis.
Technetium pertechnetate scan may show the enhancement of diverticulum if gastric mucosa is present.
Intussusception
Occurs in young children (aged <2 years).Sudden onset of colicky pain; between episodes of pain the child is calm.A sausage-shaped mass may be palpable in the right lower quadrant.
Barium enema may demonstrate the intussusception with a coil-spring sign at the point of bowel invagination.
Crohn's disease
Young adult with fever, nausea, vomiting, diarrhoea, right lower quadrant pain, and localised tenderness.
CT scan may show intra-abdominal abscess.Contrast study of the small bowel and colon may show stricture or a series of ulcers and fissures (cobblestone appearance) of mucosa.
Peptic ulcer disease
May or may not have a history of peptic ulcer disease.Pain is abrupt, severe in intensity, and may be localised to right lower quadrant.
Erect CXR and abdominal x-ray may show free air under the diaphragm
Right-sided ureteric stone
Pain is usually colicky in nature and severe in intensity. May be referred to the labia, scrotum, or penis and associated with haematuria.Fever usually absent.
Urinalysis positive for blood.Leukocytosis usually absent.Abdominal x-rays or tomogram may show calcified stone.Pyelography and CT scan without oral and IV contrast confirm the diagnosis.
Cholecystitis
Pain and tenderness are usually in the right upper quadrant. In one third of patients the gallbladder can be palpable. [41]
Abdominal ultrasound shows thick wall with peri-cholecystitis collection, and tenderness is present over gallbladder area (Murphy's sign).Hepatobiliary iminodiacetic acid scan will show non-visualisation of gallbladder at >4 hours.
Urinary tract infection
Pain and tenderness is usually in suprapubic area associated with burning micturition.Acute right-sided pyelonephritis may present with fever, chills, and tenderness at the right costovertebral angle.
Urine microscopy and culture confirm presence of bacteria.
Primary peritonitis
Most patients present with abrupt abdominal pain, fever, distension, and rebound tenderness.History of advanced cirrhosis or nephrosis.
CT scan may show fluid in the abdomen.Peritoneal fluid shows >500/microlitre count and >25% polymorphonuclear leukocytosis.
Pelvic inflammatory disease
Occurs in females usually aged between 20 and 40 years.Presents with bilateral lower quadrant tenderness, usually within 5 days of the last menstrual period.Purulent discharge from cervical os.
Endocervical swab may confirm the pelvic inflammatory disease due to Chlamydia trachomatis. [42]
Ruptured Graafian follicle (mittelschmerz)
Mid-menstrual cycle, brief period of lower abdominal pain not usually associated with nausea and vomiting and fever.Tenderness is usually diffused not localised.
Clinical diagnosis. No investigation indicated.
Ectopic pregnancy
Female within childbearing age presents with missed menstrual period, right lower quadrant pain, or pelvic pain with some degree of vaginal bleeding or spotting. Cervical motion tenderness may be present on pelvic examination.
HCG hormone level is high in serum and in urine.Ultrasound reveals presence of mass in fallopian tubes.
Ovarian torsion
Female with right lower quadrant pain. Occasionally presents with mass in the right lower quadrant.
Ultrasonography shows ovarian cyst and decreased blood flow.

Acute aspiration

Acute respiratory distress syndrome
Seen in the setting of sepsis or trauma. No difference in signs and symptoms from aspiration pneumonitis, which can itself lead to ARDS. [38]
Bilateral alveolar infiltrates can be indistinguishable from those seen in aspiration pneumonitis.
Asthma exacerbation
Wheezing is paroxysmal and intermittent and usually diffuse. It decreases after bronchodilators, is polyphonic, and is characterised by many different pitches. Cough is triggered by exercise, cold, sleep, and allergens. Patient may have hx and/or FHx of atopy or asthma. [39]
Pulmonary function tests usually show reversible obstructive ventilatory impairment. [39]
Cystic fibrosis with exacerbation
Wheezing presents early in life, with accompanying poor weight gain, diarrhoea, and recurrent sinus and pulmonary infections. Nasal examination may reveal polyps. Cough is productive and wet, suggesting a suppurative process such as bronchiectasis. Patient may have FHx of bronchiectasis. [39]
Sweat chloride test shows elevated level of chloride. Chest x-ray may reveal bronchiectasis, but CT scan is more sensitive. [40]
COPD exacerbation
Wheezing is diffuse and associated with increased mucus production and hx of progressive dyspnoea.
Chest x-ray shows peribronchial cuffing and hyperinflation.
Infectious pneumonia
No difference in signs and symptoms.
Chest x-ray may show lobar consolidation.
Congestive heart failure
Orthopnoea, paroxysmal nocturnal dyspnoea, and right upper quadrant discomfort may be features. Sputum, if present, is usually frothy. Fever is usually absent. [41]S3 gallop rhythm has up to 50% sensitivity but 90% specificity. Pulsus alternans, characterised by evenly spaced strong and weak peripheral pulses, is pathognomonic of severe left ventricular failure. [41] [42]
Chest x-ray may reveal enlarged pulmonary vessels, cardiomegaly, and pulmonary oedema; the infiltrates improve quickly after diuresis.Brain natriuretic peptide >100 nanograms/L (>100 picograms/mL) makes a diagnosis of heart failure with sensitivity of 90%, specificity of 76%, and predictive accuracy of 83%. [43]
Acute interstitial pneumonitis
No differentiating symptoms or signs, but they develop over a few days to several weeks. In some cases, it is idiopathic (Hamman-Rich syndrome); or it can be caused by collagen vascular disorders, cytotoxic drugs, or infectious aetiologies; or it can develop in a pre-existing idiopathic pulmonary fibrosis. [36]
Bilateral alveolar infiltrates can be indistinguishable from those seen in aspiration pneumonitis.Bronchoalveolar lavage cell count reveals >10% neutrophils, and lung biopsy shows diffuse alveolar damage. [36]
Acute bronchiolitis obliterans organising pneumonia
No differentiating symptoms or signs. Can be idiopathic or due to collagen vascular disorders, drugs, radiation, or infection. [36]
Bilateral alveolar infiltrates can be indistinguishable from those seen in aspiration pneumonitis. Bronchoalveolar lavage cell count in organising pneumonia may reveal neutrophilia and sometimes lymphocytosis (but <25% lymphocytes) with eosinophilia (but <25% eosinophils). [36]
Acute eosinophilic pneumonia
No differentiating symptoms or signs, but duration of illness is usually <1 week. Can be idiopathic or caused by drugs. [36]
Bilateral alveolar infiltrates can be indistinguishable from those seen in aspiration pneumonitis. Bronchoalveolar lavage cell count reveals >25% eosinophils. Eosinophilic pleural effusion is rare. Eosinophilic infiltration and diffuse alveolar damage may be seen on lung biopsy. [44]
Acute hypersensitivity pneumonitis
No differentiating symptoms or signs, but usually develops within 4 to 6 hours after inhalation of an organic agent. Caused by environmental and work-related antigens. [36]
Bilateral alveolar infiltrates can be indistinguishable from those of aspiration pneumonitis. Granulomatous and cellular pneumonitis with diffuse alveolar damage may be seen on lung biopsy. Bronchoalveolar lavage cell count shows lymphocytosis (>25%) and sometimes neutrophilia (<10%). [36]
Diffuse alveolar haemorrhage
Haemoptysis is absent in 33% of patients. Causes include vasculitis, collagen vascular disorders, anti-basement membrane antibody disease, coagulopathies, antiphospholipid antibody syndrome, and diffuse infections. [36]
Bilateral alveolar infiltrates can be indistinguishable from those of aspiration pneumonitis. Pulmonary capillaritis, bland haemorrhage, and diffuse alveolar damage seen on lung biopsy.Bronchoalveolar lavage shows progressively bloodier return. Cytology shows RBCs and haemosiderin-laden macrophages.Urinalysis may show proteinuria, haematuria, and red cell casts in cases of pulmonary-renal syndromes. [36]
Neurogenic pulmonary oedema
No differentiating symptoms or signs. Usually develops within minutes to hours after acute central nervous system injury such as seizures, head injury, or cerebral haemorrhage. Resolves within 48 to 72 hours. [45]
Bilateral alveolar infiltrates may be indistinguishable from those seen in aspiration pneumonitis. [45]

Acute asthma exacerbation in adults

Foreign body/obstruction
May cause a localised wheeze, depending on site of obstruction.History may reveal a foreign body aspiration.No significant improvement with bronchodilators.
If the foreign body is radio-opaque, it may appear on a plain x-ray. Otherwise, a CT scan of the chest may suggest an endoluminal obstruction.Fibreoptic bronchoscopy is the definitive test for diagnosis and treatment of a foreign body in the airway.
Vocal cord dysfunction
Difficult to diagnose.May occur independently from or concomitantly with asthma.More common in young females.Wheezing is often more prominent over the neck.Symptoms may be precipitated by stress and patients may feel worse with bronchodilators as they could heighten anxiety.Frequently inspiratory wheezing.
A video laryngostroboscopic examination may show paradoxical vocal cord movement.The classically observed pattern consists of adduction of the anterior two-thirds of the vocal cords with a posterior diamond-shaped chink. This occurs during inspiration but can be present during the entire respiratory cycle and can also be observed on the flow-volume loop as flattening of the inspiratory limb.
Cardiac dysfunction
History of left ventricular dysfunction with signs and symptoms of heart failure including crackles and rales on auscultation of the lungs and peripheral oedema.
Presence of pulmonary oedema on chest radiographs should guide the clinician to a cardiac cause of symptoms.Brain natriuretic peptide (BNP) may help to exclude cardiac cause if <100 nanograms/L (100 picograms/mL). [28]
Anaphylaxis
More stridor than wheezing.A history of an environmental exposure to a possible stimulus for anaphylaxis is essential.
No differentiating tests.
Emphysema/COPD
History of smoking that usually exceeds 20 pack-years.COPD exacerbations and asthma exacerbations are clinically similar, with cough, shortness of breath, and wheezing the typical symptoms.Patients with asthma are more likely to have episodic chest symptoms, night-time chest symptoms, and chest symptoms after exposure to allergic triggers.Patients with COPD are more likely to have a daily morning cough that produces mucus, and persistent chest symptoms throughout the day.
Patients with asthma will present with evidence of bronchial hyperreactivity and reversibility on pulmonary function tests more frequently than patients with COPD.
Carcinoid syndrome
May have associated flushing, diarrhoea, or right-sided heart failure.
Patients have significantly raised serum levels of serotonin or its metabolites, of which the most important is 5-hydroxyindoleacetic acid.
Pulmonary embolism
Wheezing is unusual with pulmonary emboli but may occur with several small emboli.Chest pain would be a differentiating feature.History of risk factors for PE, including immobilisation, previous DVT/PE, or cancer, in a patient with a sudden onset of dyspnoea should prompt additional testing for PE.
A low- or intermediate-probability Well's score along with a negative D-dimer assay may rule out this diagnosis.If clinical suspicion warrants, a CT pulmonary angiogram study or V/Q scan can be performed. [29]
Allergic bronchopulmonary aspergillosis (ABPA)
Occurs in 1% to 2% of asthma patients.ABPA is a hypersensitivity reaction in patients with asthma or cystic fibrosis that may cause bronchial obstruction, mucus production, and wheezing.Differential symptoms include fever, haemoptysis, and expectoration of brown mucus plugs.
Chest radiograph may show pulmonary infiltrates or evidence of bronchiectasis.Skin test reactivity or serum antibodies to Aspergillus are present.Serum IgE is typically >1000 nanograms/mL and there is generally a peripheral blood eosinophilia of >500/mm^3. [30]
Pneumothorax
Can present with symptoms similar to an asthma exacerbation.Shortness of breath and chest tightness are common symptoms of pneumothoraces.
If clinical suspicion warrants, a chest radiograph can be performed to assess for a pneumothorax.

Acute asthma exacerbation in children

Inhaled foreign body
Sudden onset of symptoms, such as cough, wheeze, or choking.Auscultation reveals differential air entry or wheeze.
Inspiratory and expiratory CXRs may reveal asymmetry of chest expansion, due to the ball-valve mechanism of the foreign body.Bronchoscopy is necessary for diagnosis and retrieval of the foreign body.
Viral-induced infantile wheezing
Onset in infancy. No associated atopy.Associated with maternal smoking.Diagnosis usually made retrospectively once the child has left the infantile age range.
Skin prick testing is negative; may provide supportive evidence but is not definitive.
Aspiration
History of vomiting and/or history of choking or coughing during swallowing (in particular, when neurodevelopmental abnormality is present).Focal signs of pneumonitis or pneumonia may be present on examination.
Focal signs of pneumonitis or pneumonia on CXR.Modified barium swallow may confirm diagnosis.
Anaphylaxis
Acute anaphylaxis may present with associated respiratory distress and wheeze. Urticaria and signs of upper airway obstruction may be present.History of environmental exposure to a possible or known anaphylactic stimulus.
Clinical diagnosis.
Cardiac failure
Other features of cardiac failure are present (tachycardia, gallop rhythm, or hepatomegaly).Associated with congenital or acquired heart disease.
Cardiomegaly on CXR.Congenital heart disease and impaired cardiac function are demonstrated on an echocardiogram.
Pneumonia
Focal signs may be present on examination and include crepitations, decreased air entry, bronchial breathing, and dull percussion note.
Consolidation on CXR.Raised WBC count, procalcitonin level, and/or CRP in bacterial pneumonia (the last 2 tests are controversial: there are no studies on procalcitonin in asthma, while CRP can also be elevated in asthma). [38]
Pneumothorax
Sudden onset of chest pain or dyspnoea.Larger pneumothoraces may have signs of decreased air entry and hyper-resonant percussion note on examination.No wheeze on auscultation.May complicate an asthma exacerbation.
Pneumothorax is seen on CXR.
Pertussis
Infection with Bordetella pertussis causes prolonged coughing (also called the '100-day cough').Spasmodic coughing may lead to post-tussive emesis.Characteristic whoop may not be evident in younger children.
Pertussis PCR test for pertussis antigen on nasal swab sample.Absolute lymphocytosis of WBC differential may be present.
Cystic fibrosis (CF)
Airway inflammation associated with CF may precipitate wheeze, cough, and respiratory distress.CF due to milder mutations may present with asthma that is difficult to control or treatment-resistant.Asthma may co-exist with CF.Failure to thrive may be present.
Sweat test: sweat chloride ≥60 mmol/L on repeat samples is diagnostic (levels of 40 to 60 mmol/L should be considered indeterminate and suspicious).
Tracheo- or bronchomalacia
Characterised by expiratory stridor.Recurrent acute episodes of stridor and dyspnoea usually present in the neonatal period and diminish during the first 2 years of life.
Bronchoscopy reveals collapse of the trachea or bronchus during expiration.
Acute bronchitis
Characterised by moist cough in combination with wheeze, and may be caused by bacterial or viral infection.Bacterial cause is suggested by purulent sputum and response to antibiotics.
In bacterial bronchitis, sputum culture commonly isolates Haemophilus influenzae or Streptococcus pneumoniae. [39]
Paradoxical vocal cord motion
Paradoxical adduction of the vocal cords during inspiration produces high-pitched inspiratory stridor and dyspnoea that may be misinterpreted as wheeze.May be spontaneous or exercise-induced.
Exercise testing may reproduce the characteristic symptoms.Spirometry during an episode demonstrates blunting of inspiratory volume loop.
Hyperventilation attack
No associated wheeze on auscultation.
No obstructive pattern on spirometry during a hyperventilation episode.
Exertional dyspnoea unrelated to pathology
Perception of breathlessness during exercise alone.
Exercise testing may help distinguish.
Croup
Characteristic sudden onset, barky cough, often accompanied by stridor and chest wall or sternal indrawing.No associated wheeze on auscultation.
Clinical diagnosis.

Acute atrial fibrillation

Atrial flutter
Clinical history and physical examination may not be useful to differentiate from AF.
ECG shows absence of P waves, presence of characteristic flutter waves that give typical saw tooth appearance in the inferior limb leads, and QRS complexes that are regularly (typically 2:1, 3:1, 4:1) irregular. View image
Wolff-Parkinson-White syndrome
Usually presents at younger age (teens or early 20s).Often precipitated by exercise.
Classic ECG has shortened PR interval and delta wave on the QRS complex, which may degenerate into AF. View imageAn electrophysiological study with view to curative ablation procedure is suggested for patients with ECG changes suggestive of Wolff-Parkinson-White syndrome who present with AF and rapid ventricular rate.
Atrial tachycardia
Clinical history and physical examination may not be useful to differentiate from AF. However, atrial tachycardia (in particular, multifocal atrial tachycardia) is more common in patients with severe COPD.
ECG shows abnormal P waves. In multifocal atrial tachycardia, there are at least 3 different morphologies of P waves. View image

Acute bronchitis

Pneumonia
Patients with pneumonia often have a higher fever than patients with acute bronchitis, may appear more ill, and have rales on lung examination.
CXR will detect an infiltrate from pneumonia that will not be present in acute bronchitis.
Allergic rhinitis
Patients with allergic rhinitis often have post-nasal drip causing a cough. On examination, acute rhinitis should be evident on nasal examination and from posterior pharyngeal drainage.
None.
Asthma
Patients with asthma have bilateral wheezing; the main difference between asthma and acute bronchitis is the chronicity of bronchospasm. In asthma, bronchospasm is recurrent and progressive.
PFT may be useful between bouts of acute bronchitis to diagnose asthma in patients who have residual obstructive findings.
Pertussis infection
Cough has characteristic whoop in children with pertussis, although this is usually not present in adolescents and adults with the infection.
Cultures, polymerase chain reactions (PCR), or direct fluorescent antibody testing for Bordetella pertussis will be positive.
CHF
Patients with CHF may cough but also have other symptoms and signs such as dyspnoea on exertion, orthopnoea, rales on lung examination, peripheral oedema, raised jugular venous pressure, and a history of cardiac problems.
CXR shows pulmonary vascular congestion and may show cardiomegaly in CHF.
Reflux oesophagitis
Aspiration from reflux oesophagitis may cause a non-productive cough that is usually chronic in nature. Burning and chest pain characteristic of reflux may be helpful in differentiating this from acute bronchitis. If wheezing is present, often it is only on the right, where aspiration is most common.
Upper GI endoscopy may show oesophageal inflammation or erosions with reflux. pH monitoring also can be helpful for detecting acid in the distal oesophagus.
Upper respiratory infection/common cold
Viral upper respiratory infections and acute bronchitis may be indistinguishable. Indeed, many advocate calling acute bronchitis a 'chest cold' to denote that viral bronchitis is often simply an extension from an upper respiratory illness. The productive cough from a common cold can be from inflammation of the trachea or bronchial tree or can result from post-nasal drainage from an upper respiratory infection.
None.
Medication/environmental exposures
Several medication or environmental exposures can also cause an acute cough. These include the use of ACE inhibitors or occupational exposures to dusts or chemicals. In many of these cases, such as ACE inhibitor use, the cough is non-productive. In occupational exposures, generally symptoms are restricted to the cough without any other systemic symptoms such as fever, headaches, or lethargy.
None; the diagnosis should be made based on history of exposure to agents that can cause a cough.

Acute cervical spine trauma

Non-traumatic neck pain
No history of trauma.May have symptoms of secondary infection (pain with fever, tachycardia), neoplasia (unrelenting pain, especially at night), or inflammation (e.g., arthritides) or have no identifiable aetiology.Infective aetiologies include meningitis, vertebral osteomyelitis, and epidural abscess.Neoplastic lesions can be primary or metastatic, and any patient with a prior history of cancer should be evaluated for recurrence before cancer can be ruled out as a cause of the neck pain.Patients with osteoarthritis and rheumatoid arthritis may have signs and symptoms of arthritis in other joints.
C-spine x-ray: cancer - single or multiple lesions with bony destruction; osteoarthritis - cervical spondylosis or normal.C-spine MRI: cancer - single or multiple lesions with bony destruction; infection - infected areas of bone (vertebral osteomyelitis) or signs of abscess (epidural abscess).CT scan: signs of meningitis.Bone scan: metastatic neoplastic lesions in the spine.Erythrocyte sedimentation rate, c-reactive protein: elevated in infection, malignancy, or inflammatory arthritis.Full blood count: elevated white blood cell count in infection.Herpes zoster immunohistochemistry: positive in varicella virus.
Degenerative cervical spine disease
No history of trauma.Symptoms may be similar to those associated with neck trauma and include axial neck pain and neurological complications such as radiculopathy and myelopathy.
C-spine x-ray: presence of degenerative joint disease or degenerative disc disease.Cervical MRI: bone destruction, spinal cord or nerve compression, intradural or epidural process.
Acquired torticollis
No history of trauma.Involuntary twisting or deviation of the neck, abnormal head posture, presence of sensory trick (patient can resolve symptoms by touching neck or face), normal neurological examination.
C-spine x-ray: usually normal.MRI brain and C-spine: usually normal. If chronic, may have cervical muscle asymmetry and nerve root compression.

Acute conjunctivitis

Dry eyes
Typically a chronic condition of adults; occurs in women more than men; usually bilateral with minimal discharge or eyelash matting; minimal injection; no discharge or lymphadenopathy. [38] [39] [40] [41] [42] [43]
Punctate staining of the cornea with fluorescein dye; Schirmer's tests with <10 mm; tear break-up time <10 seconds.
Blepharitis
Typically a chronic condition of adults; women more than men; usually bilateral with minimal discharge or eyelash matting; minimal injection; no discharge or lymphadenopathy; presence of meibomian gland dysfunction, eyelid margin telangiectatic vessels; collarets along the lashes. [38] [39] [40] [41] [42] [43]
Tear break-up time <10 seconds.
Episcleritis
Unilateral more common than bilateral; typically segmental injection; no discharge or eyelid matting; minimal discomfort. [38] [39] [40] [41] [42] [43]
No definitive tests; recurrent, bilateral, or persistent cases require blood tests to rule out a systemic inflammatory disease.
Contact lens overwear
History of sleeping in contacts; multiple recurrences; light sensitivity. [38] [39] [40] [41] [42] [43]
No definitive tests.
Iritis (uveitis)
Pain and light sensitivity more pronounced than irritation; unilateral more common than bilateral. [38] [39] [40] [41] [42] [43]Red and white blood cells, as well as flare (effect caused by an increase in the protein content of the aqueous) usually seen with slit-lamp examination.
No definitive tests; recurrent, bilateral, or persistent cases require blood tests to rule out a systemic inflammatory disease.
Acute angle-closure glaucoma
Adult typically older than 40 years; nausea and vomiting may be be present as well as a deep, dull, periocular headache; unilateral; pain associated with decreased vision; mid-dilated, unreactive pupil; presence of an afferent pupillary defect. [38] [39] [40] [41] [42] [43]
Marked elevation in intraocular pressure (normal <22 mmHg); thin corneas (pachymetry <520); afferent pupillary defect.

Acute cystitis

Pyelonephritis
Fever, nausea, and vomiting. On physical examination, flank tenderness is considered pathognomonic for pyelonephritis.
Elevated WBC, and positive blood cultures.
Vaginitis
Significant pruritus or vaginal discharge.
Positive potassium hydroxide (KOH) prep/wet mount and elevated vaginal pH.
Interstitial cystitis
Failure to respond to antibiotics.
Negative urine cultures.
Chlamydia urethritis
None.
Negative urine culture, positive polymerase chain reaction (PCR) test for Chlamydia.

Acute epididymitis

Testicular torsion
Usually presents with sudden-onset severe unilateral scrotal pain.Should be considered as a differential diagnosis in all male patients presenting with acute scrotal pain, particularly when there is an absence of symptoms and signs relating to an infectious cause, such as urinary frequency, painful micturition, and urethral discharge.Occurs more frequently in adolescents, but can occur in all age groups.
Negative Prehn's sign: there is no pain relief when the affected hemiscrotum is elevated.Colour duplex ultrasonography has been shown to be useful in differentiating between torsion and inflammatory pathology in cases where the history and clinical findings are equivocal. [15]However, there should be no delay in performing scrotal exploration in cases where testicular torsion is considered a likely differential diagnosis.
Acute idiopathic scrotal oedema
Usually affects the paediatric population, but has been reported in adults. [16]Acute onset of redness and oedema, but usually painless.Can be unilateral or bilateral.
Usually diagnosed clinically. Ultrasonography can be used to confirm the diagnosis.
Infected hydrocele
History of pre-existing hydrocele.
Ultrasonography confirms the presence of a hydrocele containing turbid fluid, with a normal appearance of, and blood flow to, the epididymis and testis.
Strangulated inguinal hernia
History of previous intermittent inguinoscrotal swelling, with or without pain.Sudden onset of pain and inability to reduce the hernia. Associated nausea and vomiting.May be difficult to palpate the testis and epididymis with a large strangulated inguinal hernia.
Usually diagnosed clinically.
Testicular tumour
Usually a painless swelling of gradual onset, but can mimic an epididymitis in some malignant presentations. This is usually due to the presence of a superior polar tumour in the rete testis.
Ultrasonography will confirm the presence of a testicular tumour.

Acute exacerbation of chronic obstructive pulmonary disease

Congestive heart failure
Patients with systolic left-sided or biventricular congestive heart failure will often have a history of heart failure. Underlying diastolic heart failure may be under-recognised.Physical examination may note signs consistent with heart failure, such as an elevated jugular venous pressure, extra heart sounds, coarse breath sounds with crackles above the lung bases, and dependent pitting oedema. [128] It may be difficult to distinguish heart failure, particularly left-sided heart failure, from an acute exacerbation of COPD.
Chest imaging may show an enlarged heart and/or pleural effusions. An elevated B-type natriuretic peptide is often present. [129] [130] An echocardiogram may be used to determine cardiac function.
Pneumonia
Many aspects of acute exacerbations including dyspnoea, cough, and sputum production may be found in patients with pneumonia and it is often not possible to differentiate without chest imaging.About 10% to 15% of patients presenting with an apparent acute exacerbation are found to have pneumonia, or other abnormalities, defined by chest imaging. [131] [132] [133] Patients with pneumonia have in general been found to experience higher fevers, more acute onset of illness, and somewhat greater severity of acute illness when compared with COPD patients without pneumonia. [131] [134]
Chest imaging in patients with pneumonia should identify changes consistent with an infiltrative process in the lung parenchyma.
Pleural effusion
Pleural effusions may exacerbate dyspnoea in patients with COPD. Physical examination may demonstrate decreased or absent breath sounds with dullness to percussion related to a pleural effusion.
Chest imaging is recommended.
Pneumothorax
Patients with COPD found to have pneumothoraces may or may not have additional signs or symptoms suggestive of a respiratory tract infection, but their presentation may closely mirror that of an acute exacerbation. Decreased breath sounds may be identified on the affected side and tracheal deviation away from the affected side and/or hypotension may be present in patients with a tension pneumothorax.
Chest imaging is recommended to exclude a possible pneumothorax in patients with more than mild episodes. [135]
Pulmonary embolism
Clinically, pulmonary embolism may present with signs and symptoms similar to an acute exacerbation of COPD, and the two are difficult to distinguish. [136] Pulmonary embolism should be considered as a cause of the acute symptoms if no other identifiable trigger for the exacerbation is evident. Persons with prior thrombo-embolic disease or underlying malignancy may be at particular risk. [136]A low systolic blood pressure and/or the inability to increase the PaO2 >60 mmHg with oxygen may indicate the presence of a pulmonary embolism.
Pulmonary embolus may be diagnosed using D-dimer assay, spiral computed tomography angiogram, or pulmonary angiography in patients with COPD. Test selection should be based on local expertise. Dopplers of the lower extremities may be considered to evaluate for deep vein thrombosis.
Cardiac ischaemia
Clinically, may be difficult to distinguish. Chest pain may be more apparent, with radiation down left side. Nausea, jaw pain, and/or diaphoresis may be present.
An electrocardiogram should be performed for patients who may require hospitalisation for care of an acute exacerbation of COPD, to identify possible cardiac ischaemia and arrhythmias. [46]
Cardiac arrhythmia
Differentiating features may include palpitations, light-headedness, loss of consciousness, and/or collapse.
An electrocardiogram should be performed for patients who may require hospitalisation for care of an acute exacerbation of COPD or who are experiencing palpitations or dizziness, to identify possible cardiac ischaemia and arrhythmias. [46]
Inappropriate oxygen therapy
While oxygen therapy is clearly indicated for many patients with COPD and acute exacerbations, excessive oxygen leads to further degradation of the patient's respiratory physiology. Exposure to oxygen leads to decrease of hypoxic vasoconstriction of arteries supplying poorly ventilated spaces, increasing the degree of V/Q mismatch and/or intrapulmonary shunt. [137] [138] An excess of oxygen may also decrease the capacity of erythrocytes to carry CO2 (Haldane effect). [139] These changes may then result in worsening of the patient's hypercarbia and respiratory acidosis.
An ABG should be performed for patients who are hypoxaemic or are receiving oxygen therapy who present with an apparent acute exacerbation of COPD.

Acute exacerbation of congestive heart failure

Pneumonia
Fever, cough, productive sputum.Focal signs of consolidation - increased vocal fremitus and bronchial breathing.
WCC: elevated.Blood cultures: positive for organism.CXR: consolidation.
Pulmonary embolism
Haemoptysis and sharp, pleuritic chest pain.Risk factors of thromboembolism (TE) include personal history of TE, family history, recent trauma, prolonged immobilisation, smoker, or OCP use.
CT pulmonary angiography: clot in pulmonary artery.
Asthma
Wheezing on physical examination.
Reduced peak flow.Spirometry: obstructive pattern, reversibility with beta-agonist inhalers
Interstitial lung disease
Progressively increasing dyspnoea.Oxygen desaturation with exercise.Fine bibasal crepitations with no other signs of heart failure.
CXR: reticular infiltrate in the late stages of disease.High-resolution CT scan: ground-glass appearance, reticular infiltrates, honeycombing, and architectural distortion.Spirometry: restrictive pattern.
Adult respiratory distress syndrome
Severe hypoxia, fine crepitations.
CXR: diffuse infiltratesPulmonary artery wedge pressure: <18 mmHg

Acute intermittent porphyria

Other conditions that cause abdominal pain
AIP symptoms are neurological rather than inflammatory, so peritoneal signs, fever, and leukocytosis are usually not as prominent as in other abdominal conditions.
FBC to eliminate leukocytosis.Presence of urinary porphobilinogen (PBG) confirms porphyria.
Delta-aminolevulinate dehydratase deficiency porphyria
Symptoms similar to AIP but extremely rare condition. [15]
Delta-aminolevulinic acid (ALA) and coproporphyrin III are markedly increased in urine, and PBG is normal or slightly increased.
Hereditary coproporphyria
Presentation the same as AIP, but associated with blistering skin lesions.
Faecal total porphyrins are substantially increased with a marked, isolated increase in faecal coproporphyrin III by high-performance liquid chromatography (HPLC). [13]
Variegate porphyria
May present as in AIP but occasionally associated with blistering skin lesions.
Increased plasma porphyrin with a diagnostic fluorescence maximum at neutral pH.Faecal porphyrins are substantially increased with a predominance of coproporphyrin III and protoporphyrin by HPLC. [16] [17]HPLC of urine or faecal sample helps differentiate AIP (predominantly uroporphyrin) from variegate porphyria (predominantly coproporphyrin).

Acute interstitial nephritis

Acute glomerulonephritis
May be asymptomatic, presenting symptoms are indistinguishable from acute interstitial nephritis (AIN).Will not respond to withdrawal of offending medication.
Urine shows RBC casts and/or large amounts of proteinuria.Renal biopsy can distinguish from AIN.
Acute tubular necrosis
May be asymptomatic, presenting symptoms are indistinguishable from AIN.A history of hypotension, fluid depletion, or exposure to a nephrotoxin known to cause acute tubular necrosis is usually present.Will not respond to withdrawal of offending medication.
Urine shows sloughed tubular epithelial cells or bland urinary sediment.
Acute vascular injury
Flank pain with gross haematuria is usually present. There may be evidence of vasculitis elsewhere in body.Will not respond to withdrawal of offending medication.
Renal blood flow scans or magnetic resonance angiography shows large vessel vascular lesions such as emboli or renal vein thrombosis.
Acute pyelonephritis
Symptoms of fever, chill, flank pain, nausea, and vomiting are present.Will not respond to withdrawal of offending medication.
Patients have pyuria with positive urine culture.
Diabetic nephropathy
Nephrotic syndrome is usually present.Patient usually has a history of diabetes.Will not respond to withdrawal of offending medication (usually an non-steroidal anti-inflammatory drug [NSAID]).
HbA1c is elevated.Renal biopsy is diagnostic and shows mesangiolysis, glomerulosclerosis, and Kimmelstiel-Wilson nodules.
Focal segmental glomerulosclerosis
Nephrotic syndrome is usually present.Will not respond to withdrawal of offending medication (usually an NSAID).Rash is absent.
Renal biopsy shows focal and segmental sclerosis of the glomeruli.HIV is a known cause, and may be positive.
Membranous nephropathy
Nephrotic syndrome is usually present.Malignancy, viral hepatitis, and syphilis are known causes.Will not respond to withdrawal of offending medication (usually an NSAID).
Renal biopsy shows thickening of basement with subepithelial electron-dense deposits.Chest x-ray or CT scan may show a mass consistent with a lung tumour.Stools may be haem-positive in cases of gastrointestinal malignancy.Hepatitis B and C serologies or rapid plasma reagin (RPR) syphilis test may be positive.
IgA nephropathy
Nephrotic syndrome is usually present.Will not respond to withdrawal of offending medication (usually an NSAID).
Renal biopsy shows IgA deposits on immunofluorescent examination.

Acute liver failure

Severe acute hepatitis
Patients may present with jaundice and coagulopathy. However, this would not be considered ALF in the absence of hepatic encephalopathy. Severe acute hepatitis should be followed very closely as this may potentially develop into ALF or subacute liver failure, depending on the time course and development of hepatic encephalopathy.
Absence of hepatic encephalopathy. According to the West Haven Criteria, hepatic encephalopathy can be categorised into 4 grades based on severity: [33] [34]Grade 1 hepatic encephalopathy is characterised by sleep reversal, mild lack of awareness, shortened attention span, and impaired computations.Grade 2 is associated with lethargy, poor memory, personality change, and the development of asterixis on physical examination.Grade 3 progresses to somnolence, confusion, disorientation, and physical findings that include hyper-reflexia, nystagmus, clonus, and rigidity.Grade 4 is characterised by stupor and coma.
Cholestasis
Jaundice may result from intra- or extrahepatic biliary obstruction as well as from intrahepatic cholestasis due to conditions such as drug-induced liver injury or a chronic cholestatic liver disease. In the setting of an acute biliary obstruction, a patient may present with shock associated with cholangitis. Key features that distinguish these presentations from ALF include absence of coagulopathy and of hepatic encephalopathy, both of which are present during ALF.
Normal PT/INR, absence of hepatic encephalopathy (according to the West Haven Criteria as mentioned above). [33] [34] In the presence of coagulopathy associated with cholestatic disorders and vitamin K deficiency, administration of subcutaneous vitamin K would improve PT/INR and may also be considered as a differentiating test.
Haemolysis
May present with jaundice characterised by an elevated unconjugated (indirect) serum bilirubin.Typically occurs in the absence of liver dysfunction; therefore, coagulopathy and hepatic encephalopathy would not be present. Exceptions to this include ALF secondary to Wilson's disease, which may be associated with a Coombs-negative haemolytic anaemia. [43] ALF secondary to autoimmune hepatitis may coincide with an acute autoimmune haemolytic anaemia. [46] Sickle cell disease may also present acutely with jaundice, haemolysis, and liver dysfunction as a result of a sickle cell hepatopathy. [47]
Normal PT/INR, peripheral blood smear, positive Coombs test, absence of hepatic encephalopathy (according to the West Haven Criteria as mentioned above). [33] [34]

Acute lymphocytic leukaemia

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Acute myelogenous leukaemia

Acute lymphocytic leukaemia
Clinically indistinguishable from AML.
Bone marrow biopsy, peripheral blood smear, immunophenotyping, and immunochemistry may be helpful in establishing the diagnosis.Blast cells are positive for deoxynucleotidyl transferase and lack staining for myeloperoxidase; also demonstrate presence of lymphoid markers.
Biphenotypic leukaemia
Palpable lymph nodes may be present.
The expression of antigens representing both the myeloid and lymphoid leukaemia in the leukaemic clone suggests biphenotypic leukaemia. Cytogenetics may show Philadelphia chromosome t(9:22).
Myelodysplastic syndrome
History of long-standing anaemia and transfusion dependence.
The distinction between high-risk myelodysplastic syndrome (MDS) and AML is artificial in that it is based on the numbers of blasts present. The estimation of blast counts can be difficult and is subjective. The blood film shows dysplasia in >10% of cells of any lineage and the bone marrow may show up to 19% blasts.Micromegakaryocytes and acquired Pelger-Huet (spectacle eye nucleus) neutrophils are specific for MDS. Associated chromosomal deletions or unbalanced chromosomal abnormalities, particularly of chromosomes 8, 7, and 5, are common. Complex cytogenetic changes may occur.The presence of dysplasia may suggest that AML has evolved from MDS.
Chronic myelogenous leukaemia blast crisis
There may be a history of preceding chronic myelogenous leukaemia (CML).
The peripheral blood film may be indistinguishable from AML but may have an excess of basophils and eosinophils.The presence of the Philadelphia chromosome t(9:22) (q34;q11) supports a diagnosis of CML but does not exclude Philadelphia chromosome-positive AML.Typically no other karyotypic abnormalities are present.
Myelofibrosis
Typically splenomegaly is present.
Blood film shows teardrop RBCs and a leukoerythroblastic film.Bone marrow biopsy shows reticulin fibrosis.
Aplastic anaemia
May have history of medications that cause aplastic anaemia, such as chloramphenicol and non-steroidal anti-inflammatory drugs.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Low percentage of blast cells in peripheral blood (<10%). Precursors are morphologically normal.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.Patients should also be evaluated for an underlying paroxysmal nocturnal haemoglobinuria and evidence of intravascular haemolysis (reticulocytosis, elevated serum lactate dehydrogenase, and indirect bilirubin, and decreased haptoglobin). A negative Coombs test is suggestive.
Drug-induced bone marrow failure
History of using medications that may cause pancytopenia such as chloramphenicol, methotrexate, and chemotherapeutic agents.Cessation of the implicated agent or administration of an antidote such as folic acid for methotrexate reverses the pancytopenia.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow will be hypocellular, and no excess of blasts are present.Megaloblastic erythropoiesis is seen with methotrexate.Bone marrow should be reassessed after holding medication.
Leukaemoid reaction
Recent history of haematopoietic growth factor treatment may be present.Appropriate treatment (i.e., stopping the growth factor) results in normalisation of the blood count.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow shows no excess of blasts but mature haematopoietic cells. Increased macrophage activity and toxic granulation of myeloid cell series may be present suggesting infections; Dohle bodies may also be seen in infections.
Vitamin B12 deficiency
May have a family history consistent with pernicious anaemia.Paresthesia is an early symptom.Glossitis and neurological signs, such as cognitive impairment or subacute combined degeneration (ataxia, decreased vibration sense, muscle weakness, and hyporeflexia), occur with severe deficiency.
Macrocytic anaemia will be present unless there is an associated iron deficiency.Peripheral blood smear shows megaloblastic changes.Serum vitamin B12 levels are low.

Acute pancreatitis

Peptic ulcer disease
Longstanding epigastric pain, which does not generally radiate to the back; reflux; heartburn; and anorexia. Identifiable causes such as non-steroidal anti-inflammatory drug (NSAID) use, Helicobacter pylori, Zollinger-Ellison's syndrome may be present.
May improve with proton pump inhibitors, lifestyle modifications, and H pylori treatment.Normal lipase and amylase.Tonometry may show evidence of reflux.Laboratory evaluation will show normal values of amylase and lipase.Endoscopic evaluation will be diagnostic after visualising erosions, erythema, or ulcers, and allows biopsies to be performed.
Perforated viscus
Will present with acute abdomen, peritoneal signs, tachycardia, and sepsis. Generally the abdomen is rigid and tender in all 4 quadrants, with guarding.
Normal lipase. May have elevated amylase (usually less marked than that seen in acute pancreatitis).Plain x-rays show sub-diaphragmatic air.
Oesophageal spasm
Dysphagia, odynophagia, weight loss, history of retrosternal pain. Physical examination may be normal.
A swallow study may demonstrate a contracted and abnormal-appearing oesophagus with increased pressures on oesophageal manometry.
Intestinal obstruction
History of abdominal surgeries (especially colon resection, caesarean sections, and aortic procedures).Hernias in the physical examination.Presents with abdominal distension (depends on the level of obstruction), tympanism, decreased bowel sounds, anorexia, emesis (quality depends on location of obstruction), obstipation, or constipation.
Normal lipase and amylase.Acute abdominal series will show ground glass appearance, air-fluid levels, distended bowel loops, absence of distal gas, pneumatosis.An abdomen/pelvic CT scan may be more diagnostic, and will show point of transition and potentially identify aetiology (such as volvulus, hernias, intussusception, masses).
Abdominal aorta aneurysm
Cardiovascular risk factors: hyperlipidaemia, tobacco, diabetes mellitus, homocystinaemia.Acute tearing-like abdominal pain, pulsating abdominal mass, hypotension, and mottled lower extremities with decreased pulses and abdominal distension.
High index of suspicion is necessary to make a rapid diagnosis and improve outcomes. In stable patients, where history and physical examination are equivocal, a CT angiography may be useful as a rapid way to make diagnosis.If too unstable for radiographic evaluation, patients usually go directly to surgery.
Cholangitis
Charcot's triad (jaundice, right upper quadrant pain, and fever) present in 70% of patients, altered mental status, and hypotension indicate biliary sepsis, usually caused by gram-negative bacteria.Patient may have a history of gallstones, peri-ampullary neoplasms, or biliary manipulation such as endoscopic retrograde cholangiopancreatography (ERCP).
Several clinical findings are present more frequently in cholangitis, such as fever (95%), right upper quadrant pain (90%), and jaundice (80%).Normal lipase and amylase.Blood cultures are usually positive, especially during episodes of chills, with Escherichia coli and Klebsiella as the most common micro-organisms isolated from infected bile. [16]
Choledocholithiasis
Severe right upper quadrant pain of sudden onset, jaundice, acholia, choluria, and hx of cholelithiasis. May occlude the common bile duct and cause pancreatitis.
Normal lipase and amylase.Ultrasound will show gallstones, stones within the common bile duct with extra-hepatic and/or intra-hepatic duct dilatation.Chemistry will show biochemical obstruction, with increased levels of total and direct bilirubin, alkaline phosphatase, gamma-GT, and a slight increase in ALT/AST but normal levels of pancreatic enzymes (especially lipase).
Cholecystitis
Pain is generally triggered after a fatty meal and localised in the right upper quadrant. More common in overweight females between 40 and 50 years of age.Anorexia, nausea, and vomiting may be present. May show a positive Murphy's sign and low-grade fever.
Normal lipase and amylase.A right upper quadrant ultrasound will show thickened gallbladder wall, stones with acoustic shadows, biliary sludge, peri-cholecystic fluid, and sonographic Murphy's sign, and allows evaluation of the duct system. Can suggest pancreatic head inflammation. May show mild leukocytosis and a very mild elevation of liver enzymes.A hepatobiliary iminodiacetic acid (HIDA) scan is diagnostic when there is no filling of the gallbladder or with delayed emptying of the radiotracer.
Viral gastroenteritis
Generalised non-specific abdominal pain, anorexia, nausea, emesis, diarrhoea, and dehydration.Is usually a self-limiting viral infection but if fever is documented, bacterial and invasive organisms should be suspected.Consider in travellers and immunosuppressed patients.Consider osmotic and secretory diarrhoea from hx.
Normal lipase and amylase.Important to obtain serum electrolytes and an FBC.Hypokalaemia and alkalosis may be seen secondary to diarrhoea, vomiting, and dehydration.Stool examination for microscopy, culture, osmolality, ova, parasites, Clostridium difficile toxin, and white blood cells may help in identifying the causative factor.
Hepatitis
Jaundice, right upper quadrant pain, anorexia, and general malaise. Choluria and acholia may be seen.Examination: tenderness to palpation over the right upper quadrant and enlarged liver.
Normal lipase and amylase.Elevated liver function tests are characteristic. AST/ALT in the range of the 1000 units/L is not rare. Serological titres can make diagnosis of aetiological cause.Radiographic studies not important for its diagnosis.
Mesenteric ischaemia
Patients are usually older, may have a history of atrial fibrillation and risk factors for peripheral vascular disease.Hypercoagulable states may lead to bowel necrosis. Pain is usually out of proportion to the finding of the physical examination.
High index of suspicion of diagnosis is necessary. Angiography and CT scan may be useful in diagnosis as well as lactic acid levels.Normal lipase. May have elevated amylase (usually less marked than that seen in acute pancreatitis).
Myocardial infarction
Pain is usually retrosternal with radiation to jaw, neck, and left upper extremity. Associated with shortness of breath, nausea, vomiting, and diaphoresis. Cardiovascular risk factors in the history.
Elevated cardiac enzymes (creatine kinase or creatine phosphokinase, troponins), ECG changes, and clinical scenario make the diagnosis.Normal lipase and amylase.Cardiac catheterisation, perfusion scans, and echocardiograms are useful during the work-up of cardiac ischaemia.

Acute pharyngitis

Epiglottitis
Severe and acute onset of sore throat.Notable change in the quality of the voice to a muffled texture.Fever and drooling of saliva from the mouth.
Direct visualisation of the epiglottis (under controlled circumstances in the operating room, with the immediate capability of intubation should the airway close), or lateral neck x-rays.View image
Retropharyngeal, peritonsillar, and lateral abscess
Sore throat, fever, neck pain, and muffled voice.Usually in children 4 years of age or younger.
Imaging studies of the neck may be required to visualise the abscess.
Infectious mononucleosis
Pharyngitis of longer than several days' duration.Adenopathy and splenomegaly.
Serum monospot positive for Epstein-Barr virus infection.Atypical lymphocytes in peripheral blood.
Diphtheria
Pharyngitis with grey membrane adherent to the pharynx.View imageCervical adenopathy.Rarely seen except in developing countries.
Culture recovery of organism.
Lemierre's syndrome
Thrombophlebitis of the jugular vein, with a mixed anaerobic abscess.Typically present in patient with systemic inflammatory response syndrome (SIRS) or sepsis.
Imaging studies of the neck demonstrate abscess.
Behcet's syndrome
Vesicles on pharynx, genital ulcers, skin lesions, and eye lesions.
Laboratory testing and imaging are not useful in making the diagnosis of Behcet syndrome, but do play a role in ruling out alternative diagnoses.
Stevens-Johnson syndrome
Preceding drug history of anticonvulsant use, recent infections, seizures, or new medications. Vesicles on pharynx.
Diagnosis is made by clinical presentation and confirmed with skin biopsy.
Kawasaki disease
Typical signs include fever, polymorphic rash, injected eyes (conjunctivitis), and mucosal erythema with strawberry tongue. Diffuse inflammation of oral mucosa.
Coronary artery aneurysms; echocardiography findings are abnormal at any stage in the course of the illness.
Hand-foot-and-mouth disease
Common childhood viral infection caused most often by coxsackievirus A16.Usually a mild illness characterised by low-grade fever, painful oral ulcers, and vesicles on the palms of the hands and soles of the feet.
Elevated WBC count, atypical lymphocytes.PCR molecular assay is an emerging diagnostic modality.
Oropharyngeal cancer
Hoarseness, dysphonia, sore throat, difficulty swallowing, vocal cord lesions on indirect laryngoscopy, and neck mass or adenopathy.
CT of the neck may be diagnostic and is essential to evaluate the extent of disease.Cytological analysis of fine needle aspirate may establish the diagnosis, although biopsy is usually required.
Aphthous ulcers
Multiple recurrent small, erythematous, round or ovoid ulcers with circumscribed margins, typically presenting first in childhood or adolescence.
Diagnosis is based on the history and clinical examination, with exclusion of a systemic aetiology; there are no specific laboratory findings.

Acute prostatitis

Benign prostatic hyperplasia (BPH)
Typically presents with a gradual reduction in urinary flow, hesitancy, frequency, and nocturia. May also present with acute retention of urine.
Clinical diagnosis with negative urinalysis. Histological examination of the prostate reveals BPH.
Prostate cancer
May present with similar symptoms to BPH (e.g., reduced urinary flow, frequency, and nocturia). Advanced cases may present with signs of metastatic disease, including bone pain.
Serum PSA elevated and may be extremely high in advanced disease.Histological examination of the prostate reveals prostatic carcinoma.
Urinary tract infection
Patients usually do not have symptoms of bladder outflow obstruction unless they have coexisting BPH or prostatic malignancy.
None. Urine cultures may be positive in acute prostatitis and UTIs.
Bladder cancer
Typically presents with haematuria (either frank or microscopic). Patients may also complain of dysuria and urinary frequency.
Urinalysis typically with haematuria, though may be negative (e.g., diluted urine sample).Cystoscopic examination of the bladder demonstrates the presence of a tumour.
Colorectal cancer
Typically presents with a change in bowel habit and, in some patients, rectal bleeding. Patients may also present with weight loss.
Endoscopic examination of the rectum and colon demonstrates the presence of a tumour.The tumour may also be demonstrated on imaging (e.g., barium enema).
Epididymitis/orchitis
Typically presents with scrotal/testicular pain and symptoms of dysuria and frequency.
Clinical diagnosis. Colour duplex ultrasonography may show enlarged and hyperaemic epididymis.

Acute pyelonephritis

Chronic pyelonephritis
Suggested by a relevant history of underlying medical problems, such as anatomical abnormalities that predispose to obstruction (e.g., kidney stones), metabolic factors (e.g., diabetes), or recurrent infections with resistant bacteria that lead to permanent renal damage evident on imaging studies.
Imaging studies often show small, irregular, scarred kidneys.
Pelvic inflammatory disease
Determined via a history of sexual intercourse; lower abdominal, pelvic, or low back pain; pain with movements; vaginal discharge; fevers or chills; abdominal or cervical tenderness.Pelvic examination may show vaginitis, urethral discharge, or herpetic ulcerations.Cervical examination may show cervicitis.
Cervical cultures can identify causative pathogens (e.g., Neisseria gonorrhoeae, Chlamydia trachomatis).Microscopic examination of vaginal discharge demonstrates neutrophils.
Pelvic pain syndrome
Recurrent symptoms, including dysuria, pain on intercourse, and pelvic pain, occur with negative cultures.Symptoms that affect primarily the bladder may be associated with a small bladder and frequent voiding.
No differentiating tests exist.
Cystitis
Does not display systemic signs or symptoms (e.g., fevers, chills, nausea, vomiting, and back pain).Often associated with dysuria and frequency.
No differentiating tests exist.
Acute prostatitis
Can be associated with anal intercourse in men. Symptoms may include dysuria, frequency, and blood in the urine, or may be mild and subacute. May recur in patients who are treated for an adequate duration (up to 3 weeks).Physical examination shows a tender, often enlarged prostate.
Microscopic analysis shows WBCs in urine obtained after prostate massage or by collection of the terminal portion of a urine sample.
Lower lobe pneumonia
Often complain of cough and pleuritic chest pain. Physical examination may show decreased breath sounds, rales, or rhonchi.
Chest radiography is useful in making the diagnosis.

Acute renal failure

Chronic kidney disease (CKD)
Reduced renal function with elevation of creatinine is chronic (>3 months), although there may be acute on chronic renal disease.
An acutely elevated serum creatinine is diagnostic of acute kidney injury and indicative of reduced clearance.There are no causes of chronically elevated serum creatinine other than reduced glomerular filtration, except for minor elevations in subjects with increased muscle mass and from certain medicines.Creatinine elevation over time provides a chronological perspective and assists in differentiating acute from chronic kidney disease.Twenty-four-hour urine study for creatinine clearance would demonstrate the level of renal function; the use of 131-I iothalamate is standard for this purpose.
Increased muscle mass
Any elevation of creatinine is minor and typically non-acute.
Acutely elevated serum creatinine is diagnostic of acute kidney injury.Minor elevations in creatinine from increased muscle mass may rarely be seen.Twenty-four-hour urine study for creatinine clearance would demonstrate normal renal function.
Drug side effect
Certain medicines such as cimetidine may lead to an elevation of creatinine that is minor and non-acute.
Discontinuing the medicine should result in normalising of the serum creatinine.Twenty-four-hour urine study for creatinine clearance should demonstrate normal function.

Acute respiratory distress syndrome

Acute exacerbation of CHF
A history of cardiac disease, acute myocardial ischaemia or infarction, or a known low ejection fraction suggests cardiogenic pulmonary oedema, as do an S3 and elevated neck veins on physical examination.
CXR: heart failure is suggested by an enlarged cardiac silhouette, a vascular pedicle width >70 mm, central infiltrates, and Kerley B lines.Brain natriuretic peptide (BNP) levels >500 nanograms/L (>500 picograms/mL) also suggest cardiogenic oedema.Echocardiography and measurement of the pulmonary artery occlusion pressure (PAOP) may be needed if the history and physical and laboratory tests do not rule out cardiogenic pulmonary oedema.
Bilateral pneumonia
A history of fever and cough with or without sputum production.Patients may have pleuritic chest discomfort.
CXR. Severe pneumonia with bilateral infiltrates mimics the radiographic appearance of ALI/ARDS.PaO2. If patients do not have severe hypoxaemia with their pneumonia, they do not have ALI/ARDS.
Acute interstitial pneumonia
Onset is usually subacute, over days to weeks.Patients are previously healthy, with the lung disease not related to a systemic illness.Some authors have termed this disease idiopathic ALI/ARDS. [19]
Meets all the clinical criteria for ALI/ARDS.Best differentiated by history.
Diffuse alveolar haemorrhage
Associated with bleeding from the small vessels of the airways (capillaritis) and seen in many conditions, ranging from autoimmune to mitral valve diseases.Almost always a reversible form of respiratory failure, once the underlying cause is known.
A syndrome of hypoxia with infiltrates on CXR.The hallmark is finding sequentially bloodier aliquots of fluid during serial bronchoalveolar lavage.Serological tests to look for autoimmune diseases may help to differentiate from ALI/ARDS. [19]
Acute eosinophilic pneumonia
Presents as mild to severe pneumonia in previously healthy people.Patients have an excellent response to IV corticosteroids. [21]
The hallmark of this disease is increased numbers of eosinophils (upwards of 50%) on bronchoalveolar lavage.
Hypersensitivity pneumonitis
A pneumonitis after inhalation of an organic antigen.Patients present with infiltrates and a pneumonia syndrome that is clinically indistinguishable from ALI/ARDS if severe.Differentiated from ALI/ARDS by clinical history of an inhalational allergen, usually of avian origin.Corticosteroids may be beneficial. [19]
No differentiating investigations.
Post-obstructive pulmonary oedema
Acute pulmonary oedema after removal of an upper airway obstruction, most commonly caused by laryngospasm.Causes an acute respiratory failure often requiring mechanical ventilation with varying levels of PEEP.The keys to differentiation are the history of upper airway obstruction, post-surgical development, and the rapid resolution of symptoms. [22]
No differentiating investigations.

Acute sinusitis

Allergic rhinitis
Ocular and/or nasal pruritus.Sneezing.Rhinorrhoea.Headache, purulent discharge, and facial pain/pressure are less common.
Allergen skin-prick testing: wheal and flare reaction after specific allergen is introduced into the skin is 3 mm larger than negative (saline) control.In vitro-specific IgE determination: specific allergen response. [18]
Non-allergic rhinitis
Heterogenous group of nasal diseases that has nasal congestion as a common factor.History of pregnancy, barometric changes, food-associated symptoms, or hypothyroidism.
Diagnosis is clinical: there are no differentiating tests.
Migraine
History of migraine.Sensitivity to light or noise.Aura.Nausea.Symptoms decrease if sitting/lying in a quiet, dark room.Absence of purulent nasal discharge.
Diagnosis is clinical: there are no differentiating tests. Radiological tests may exclude features of acute bacterial sinusitis.
Adenoiditis
Difficult to differentiate in paediatric population as both conditions have similar symptoms.
Nasal flexible endoscopy can be used to determine the source of infection, either from the adenoids or from the sinuses.
Rhinosporidiosis and rhinoscleroma
Numbness of nasal cavity and face.Lack of expected bleeding of nasal cavity when traumatised during physical examination.Necrosis of nasal mucosa.
Rigid nasal endoscopy should be performed without anaesthesia and decongestant of the nasal cavity, to evaluate for lack of sensation or bleeding when endoscope is pressed against nasal mucosa.

Acute tubular necrosis

Pre-renal azotaemia
Oliguria is much more frequent.
Urea-to-creatinine ratio is >20:1.Urinalysis: osmolality is normal, sodium levels, ratio of urine to plasma creatinine.Ratio of urine to plasma creatinine levels are high and the urinary sodium concentration is low.
Intrinsic renal azotaemia
Patients with glomerular disease typically present with proteinuria and microscopic haematuria.
Urinalysis shows proteinuria and microscopic haematuria.

Acute varicella-zoster

Smallpox
Has more prominent fever and more noticeable constitutional symptoms than varicella.Greatest number of lesions are on face and extremities (centrifugal distribution), and lesions present at the same stage in development. [57]
PCR test for smallpox will be positive.PCR test for varicella-zoster virus (VZV) will be negative.Review history of recent smallpox vaccine or other possible exposures. Since natural transmission has been eradicated, new cases would more likely occur through laboratory exposure or as an act of bioterroism. If smallpox is considered a possible diagnosis, immediate consultation should be sought and the patient should be placed in immediate isolation (standard, contact, and airborne). The patient should not be permitted to leave isolation until smallpox has been excluded as a diagnostic possibility. Consultation with local health departments is also highly recommended.
Herpes zoster infection (shingles)
Commonly presents in adulthood, particularly after the age of 60.Rash typically follows a dermatomal distribution of a cranial nerve or dorsal root ganglion.
Varicella zoster is a clinical diagnosis based on examination of the rash and history of exposure. Differentiating tests are not usually indicated.
Herpes simplex virus infection
Usually affects the mucous membranes of the oral or genital region but skin infections, usually localised, can also be observed.
Laboratory tests positive for herpes simplex virus (HSV) 1 or HSV 2.
Stevens-Johnson syndrome/toxic epidermal necrolysis
Lesions can look like targets initially but eventually become flaccid blisters.A large proportion of patients also present with diffuse erythema (erythroderma) and a significant number of patients complain of pain in involved areas.Blisters can become confluent and are associated with a positive Nikolsky sign (epidermal layer easily sloughs off when pressure is applied to the affected area). [58]
Patients often have a history of exposure to an agent (medication) associated with the condition.Skin biopsy can be helpful; however, most often the diagnosis is made on clinical presentation. [59]
Monkeypox
Recent travel to Africa or recent exposure to exotic pets is likely to be present. [60]Lesions present in similar stages (monomorphic) and are found on the palms and soles of the feet.Also associated with lymphadenopathy, which is rarely found in varicella. [61]
PCR test for monkeypox will be positive.

Addison's disease

Adrenal suppression due to corticosteroid therapy
Hx of long-term corticosteroid therapy. Recent dose alteration, non-compliance with medication, or concurrent infection.May have Cushingoid appearance.No hyperpigmentation.
Low ACTH due to hypothalamic-pituitary-adrenal axis suppression.
Secondary or tertiary adrenal insufficiency (pituitary or hypothalamic lesions)
Hx of known pituitary or brain lesion. Symptoms related to other hormonal deficiencies or excess.
Low ACTH level.Pituitary hormone abnormalities: TSH, prolactin, FSH, LH, GH.CT or MRI brain showing lesion in the pituitary gland or hypothalamus.
Haemochromatosis
Hyperpigmentation rarely involves mucosa.
Transferrin saturation is increased (50% to 100%) and serum ferritin is substantially elevated (>1.1 to 7.4 micromol/L [90 to 600 mg/dL or 900 to 6000 micrograms/L]).
Hyperthyroidism
Tremor, nervousness, tachycardia.Unexplained weight loss without symptoms (apathetic hyperthyroidism).
Elevated T3 and free T4 levels.TSH is suppressed.Radio-iodine scan shows increased uptake in areas of excess thyroid hormone production in toxic nodular goitre and Graves' disease.
Occult malignancy
Varies with the malignancy type.
Varies with the malignancy type.
Anorexia nervosa
Fear of gaining weight, disturbed body image, weight loss, amenorrhoea.
Normal or elevated serum cortisol.Low sex steroids, LH, and FSH.

Adenocarcinoma of unknown primary site

Squamous or neuroendocrine carcinoma of unknown primary
There may be no differences in signs and symptoms.
Pathological evaluation reveals non-adenocarcinoma malignant cells.Work-up and treatment strategies will now focus on the specific pathological subtype identified.

Adhesive capsulitis

Posterior glenohumeral dislocation
Posterior shoulder dislocations usually occur after a traumatic event and are also traditionally attributed to electrocution or seizure.Acute onset of pain and immediate severe loss of motion help differentiate from adhesive capsulitis.
Axillary view plain radiograph will show a posterior shoulder dislocation.
Rotator cuff injury
Pain associated with decreased range of motion is common. Pain is typically aggravated by overhead activities.Decreased active range of motion on physical examination, but should have normal or near-normal passive range of motion.Pain and weakness on affected side elicited with provocative manoeuvres.
Shoulder MRI will show evidence of rotator cuff tear.
Subacromial rotator cuff impingement
Typically causes pain with shoulder elevation between 60° to 120° due to the rotator cuff tendons compressing against the anterior acromion and coracoacromial ligament (painful arc syndrome).There may be weakness due to pain.
Shoulder MRI may show evidence of inflammation in the subacromial space.
Proximal biceps tendonitis
Tenderness at bicipital groove.Pain in the anterior region of the shoulder with Speed test (resisted forward arm flexion with the elbow extended) or Yergason test (resisted forward supination).
MRI may reveal a subluxated long head of the biceps tendon, or demonstrate degeneration within the proximal biceps tendon.
Labral tears
Pain and decreased range of motion is common.Weakness is not a presenting symptom.Pain elicited with active compression test (resisted arm elevation with the arm 15° adducted, forward flexed parallel with the floor and maximal pronation).
MRI or MR arthrograms demonstrate glenoid labral tears.
Acromioclavicular joint arthrosis
Anterior shoulder pain.Usually have pain with cross arm adduction, and no limitation of passive range of motion.
Either plain film radiographs or MRI will demonstrate degeneration of the acromioclavicular joint, distal clavicle osteolysis, and cystic formation at the end of the clavicle.Although features suggestive of acromioclavicular joint arthrosis may be present on imaging, clinical examination can be normal.
Cervical spine neuropathy or myelopathy/Degenerative cervical spine disease
Shoulder pain and decreased motion due to cervical spine pathology is usually accompanied by neck pain and/or radiating pain, numbness, or paresthaesias down the arm. Weakness or difficulty with fine motor skills involving the hand may also be reported.Full sensory, motor, and reflex examinations as well as cervical spine examination will usually manifest symptoms and signs outside the shoulder.
Plain film radiographs may demonstrate degenerative changes in the cervical spine as well as vertebral body subluxation.MRI of the spine may confirm the radiographic findings and show evidence of cervical nerve root compression.

Adrenal suppression

Primary adrenal insufficiency
Features associated with elevations of ACTH, such as mucosal or cutaneous hyperpigmentation, may be present.Stigmata of autoimmune disorders (e.g., vitiligo) associated with autoimmune adrenal insufficiency may be present.Cushingoid features such as moon facies, dorsocervical fat pad, centripetal obesity, or striae are absent.No history of exogenous corticosteroid use.May be a history of tuberculosis or anticoagulant use.
Hyperkalaemia may be present.Serum ACTH is high.Urine screen for exogenous corticosteroids is negative.Computed tomography of adrenals may show infiltrative or haemorrhagic disease.
Pituitary compression, tumour, head trauma, and surgery (non-Cushing's)
Headaches and visual loss may occur.Cushingoid features such as moon facies, dorsocervical fat pad, centripetal obesity, or striae will be absent.Patient may have a history of head trauma or surgery affecting the pituitary.
Computed tomography or magnetic resonance imaging may show compression.Urine screen for exogenous corticosteroids is negative.
Corticosteroid withdrawal syndrome
Poorly understood. Characterised by a variety of vague symptoms such as fatigue, abdominal pain, and myalgias, which are very similar to those of adrenal insufficiency.However, when adrenal function is evaluated, these patients demonstrate normal adrenal function and reserve. They are therefore not in danger of adrenal crisis if corticosteroids are discontinued, but many are reluctant to taper treatment. Appropriate action requires a great deal of discussion between patient and physician. There are no well-controlled studies of corticosteroid withdrawal syndrome.
ACTH or other stimulation tests show normal adrenal reserve.If testing shows no evidence of adrenal insufficiency, symptoms are likely due to corticosteroid withdrawal syndrome.

Alcoholic liver disease

Hepatitis B virus infection
Often asymptomatic.History may reveal high-risk behaviour (e.g., illicit intravenous drug use, multiple sexual parters) and absence of chronic heavy alcohol use.May present as acute hepatitis B infection in adults and sometimes can be fatal from complications such as acute liver failure.Patients with chronic hepatitis B may develop complications such as cirrhosis, hepatocellular carcinoma (HCC), or liver failure.
Serum test positive for hepatitis B surface antigen (HBsAg), hepatitis B virus DNA, or anti-hepatitis B core antigen-IgM antibody.In patients with co-existing ALD and HBV but without cirrhosis, ALT is usually higher than AST.
Hepatitis C virus infection
History may reveal high-risk behaviour (e.g., illicit injection drug use) and absence of chronic heavy alcohol use.Most patients are asymptomatic.In advanced disease, patients exhibit signs and symptoms related to chronic liver injury from hepatitis C such as jaundice, ascites, spider angiomata, and constitutional complaints.
Serum test positive for anti-hepatitis C virus antibody and hepatitis C virus RNA PCR.Most patients have fluctuating elevation of ALT and AST.In patients with co-existing ALD and HCV but without cirrhosis, ALT is usually higher than AST.
Hepatitis A virus infection
History suggestive of exposure (e.g.,use of contaminated food/water, travel to endemic area, homosexual activity) and absence of binge alcohol use.Symptomatic patients may present with abrupt-onset fever, abdominal pain, malaise, and jaundice. Common examination findings are hepatomegaly and clinical jaundice.
Serum test positive for anti-hepatitis A virus-IgM antibody with marked elevation of serum transaminases.
Cholecystitis
Acute RUQ abdominal pain, with positive Murphy's sign (pain with inspiration beneath palpation at costal margin).
Ultrasound of gallbladder is the initial test.Nuclear medicine hepatobiliary scan may be helpful in cases where diagnosis is unclear.
Hepatic vein thrombosis
Variable chronicity of presentation but classic triad of abdominal pain, hepatomegaly, and ascites is seen.
Ultrasound of liver with Doppler study can show obstruction, thrombosis, collaterals, and hyperechoic cords replacing normal venous architecture.CT abdomen with contrast might be more precise for this diagnosis.
Acute liver failure
Patient with acute symptoms and signs of acute fulminant hepatic deterioration, coagulopathy, encephalopathy, and sometimes cerebral oedema.Often related to ingestion of hepatotoxic drug (e.g., paracetamol).
Severe elevation of AST and ALT with prolonged INR and PT.Serum ammonia may be dramatically elevated.Liver biopsy may be diagnostic but is contra-indicated in coagulopathy, unless done by transjugular approach.
Haemochromatosis
Presenting features include fatigue, arthralgias, and diabetes mellitus.Characteristic skin bronzing may be present.
High iron saturation (>45% transferrin saturation) and high ferritin.Positive haemochromatosis gene mutation.Liver biopsy shows excessive iron deposition in hepatocytes.High hepatic iron index.
Wilson's disease
Patients may have neurological manifestations similar to parkinsonism, and psychological manifestations such as psychosis.Kayser-Fleischer rings on slit-lamp eye examination may be present.
Increased urinary copper, decreased serum ceruloplasmin.Liver biopsy shows excessive copper deposition by copper measurement.
Drug- or toxin-induced hepatitis
History of exposure to hepatotoxic drugs or toxins.Examination may range from mild and non-specific to fulminant hepatic failure.
Liver biopsy may show evidence of hepatocellular injury or cholestatic or mixed pattern of liver injury.
Autoimmune hepatitis
History of immune dysregulation, genetic predisposition, or female sex.Constitutional symptoms are similar to those of alcoholic liver injury.
There may be positive or elevated ANA, anti-smooth muscle antibody, or anti-liver, anti-kidney microsomal antibodies.Liver biopsy shows evidence of hepatocellular inflammation with plasma cell infiltrates and interface hepatitis with plasma cell infiltrates.
Wernicke's encephalopathy
Usually presents with abrupt symptoms of confusion, short-term memory loss, eye movement disorders (nystagmus, gaze palsies, and ophthalmoplegia) in a patient with chronic malnutrition.Low thiamine intake.
Clinical diagnosis.
Biliary obstruction
Symptoms associated with biliary obstruction may include RUQ pain, fever/chills, jaundice, pruritus, nausea, and vomiting.
Ultrasound abdomen (also CT or MRI of abdomen) may show dilation of biliary tract.

Alcohol abuse

Other psychiatric disorders
Symptoms of alcohol dependence (including those of intoxication/withdrawal) may be confused with symptoms of other psychiatric disorders. Furthermore, several psychiatric disorders (e.g., schizophrenia, bipolar disorder, PTSD) can be comorbid with alcohol abuse and dependence.Differentiating signs and symptoms depend on the type of psychiatric disorder present. Definitive diagnosis is often difficult. Observation over days to weeks to months may be necessary to establish underlying psychiatric diagnoses in people continuing to actively use alcohol.
DSM-IV-TR criteria for non-substance use psychiatric disorders. [1]
Other substance use disorders (especially sedatives)
Sedating substances or medications (e.g., benzodiazepines, barbiturates, opioids) may have significantly longer-lasting effects than alcohol.Use of such substances with alcohol may pose a significant risk for overdose complications (stupor, coma, respiratory depression).
DSM-IV-TR criteria for substance use disorders other than alcohol. [1]Urine and/or blood toxicologies indicating presence of other substances.

Alcohol withdrawal

Sympathomimetic intoxication
Several drug intoxications can produce a sympathomimetic response which may include hypertension, tachycardia, elevated body temperature and sweating.
Qualitative drug screen.
Hepatic encephalopathy
Patients present with sleep disturbances and/or neurological symptoms like bradykinesia, asterixis, or focal neurological symptoms.
Abnormal LFT, abnormal chemistry panel (from use of medications in chronic liver disease resulting in low sodium or low potassium) or increase in ammonia levels.
Encephalitis
Patients usually present with abnormalities of the brain parenchyma, which may include but not limited to hemiparesis, sensory, or other motor deficits, and altered mental status.
Lumbar puncture, blood cultures, and FBC to assess leukocytosis or leukopenia; electrolyte panel for abnormal electrolytes like hyponatraemia. PCR and serology testing can be done based on suspected pathogens.
Meningitis
Fever, nuchal rigidity, and change in mental status are common features although not all patients present with this triad. Other features include but not limited to photophobia, skin rash, or cranial nerve palsies.
Lumbar puncture, blood cultures, and FBC to assess leukocytosis or leukopenia; electrolyte panel for abnormal electrolytes like hyponatraemia.
Hypoglycaemia
Symptoms include but are not limited to tremor, anxiety, palpitations, and neuroglycopenic symptoms, such as drowsiness, fatigue, headache, and loss of consciousness.
Symptoms commonly occur when blood glucose levels fall below 55 mg/dL and cognitive dysfunction can be seen in normal subjects at levels below 50 mg/dL. [16] [17]
Wernicke's encephalopathy
Likely clinical features are mental confusion, gait ataxia, and ophthalmoplegia.
There are no tests that are available in the emergency setting. Routine workup for acute delirium should be done to rule out other causes.CT or MRI may help to exclude other causes and show lesions in midbrain and periventricular region. Diagnostic imaging should not be used to decide treatment for Wernicke's encephalopathy in an emergency setting. [18] [19]
Schizophrenia
Onset is usually insidious and is preceded by social withdrawal, lack of interest, poor hygiene, and bizarre thinking. Onset is usually in early adulthood. [20]
Laboratory tests are not specific to diagnosis of schizophrenia and the accepted criteria for diagnosis come from Diagnostic and statistical manual for mental disorders, fourth edition test revision (DSM-IV-TR).
Benzodiazepine withdrawal
Symptoms are more subtle and depend on the half-life of the medication. The onset may vary from 2 days to a week. Symptoms include panic attacks, tremors, hallucinations, delusions, seizures, and hypothermia. [21]
This is a clinical diagnosis and no laboratory test is used to identify this syndrome.
Opioid withdrawal
Symptoms vary from mild drug craving to abdominal cramps, tachycardia, tachypnoea, and elevated blood pressure. [21]
This is a clinical diagnosis and no laboratory test is used to identify this syndrome.
Anticholinergic poisoning
History of anticholinergic ingestion or no prior history of alcohol abuse. Symptoms include elevated heart rate, dry skin, increased temperature, agitation, and delirium. [21]
Toxicological screening is not very helpful in anticholinergic poisoning.
Thyrotoxicosis
Is more common in women in early adulthood and is characterised by heat intolerance, muscle weakness, proptosis, and lid lag that helps to distinguish from other diseases. Nervousness, gastrointestinal hypermotility, hair loss, and cardiovascular manifestations are common. [22]
Low levels of thyroid-stimulating hormone (TSH) and elevated T3 and T4 in Graves' disease and elevated T3 in T3 toxicosis. A radioactive iodine scan is helpful in identifying the pattern of uptake in the thyroid gland.
Head injury
Patient or witness report of injury; may be loss of consciousness, amnesia, and obvious signs of trauma; may also be evidence of alcohol intoxication, so high level of suspicion of trauma recommended in these patients. [23]
Urine toxicology screen will indicate if the subject has been drinking; however, it may not exclude a diagnosis of head injury. CT scan can be diagnostic.
Somatisation disorders
Somatic symptoms in a patient with no medical findings (e.g., pseudoseizures which may mimic alcohol withdrawal seizures).Usually associated with anxiety or affective disorders. [24] [25]
There are no diagnostic tests for distinguishing these conditions. The distinction is best made in consultation with a psychiatrist.

Allergic bronchopulmonary aspergillosis

Asthma exacerbation
Although mucus production may increase with asthma, brown mucus plugs and haemoptysis are unlikely.
Skin test for sensitivity to Aspergillus fumigatus: negative.Serum total IgE: in non-allergic asthma, not elevated when patient is not taking systemic corticosteroids (which decrease IgE levels).Serum-specific IgE and serum-specific IgG to A fumigatus: not elevated.
Non-ABPA infectious exacerbation of cystic fibrosis
Clinically there is no differentiating sign or symptom.
Serum total IgE: not elevated.Serum-specific IgE and IgG to A fumigatus: not elevated.CXR: no new infiltrates from baseline.Skin test for sensitivity to A fumigatus: negative.
Chronic eosinophilic pneumonia (CEP)
Similar clinical features to ABPA.Asthma accompanies or precedes the illness in 50% of cases. [33]Occurs predominantly in women and non-smokers; cases have been reported after radiotherapy for breast cancer. [34] [43]
CXR: bilateral peripheral or pleural-based infiltrates, described as the photographic negative of pulmonary oedema, are virtually pathognomonic for chronic eosinophilic pneumonia (CEP).Lung biopsy: CEP is characterised by interstitial and alveolar eosinophils and histiocytes. Fibrosis is minimal, and bronchiolitis obliterans organising pneumonia is a commonly associated finding. [33]
Churg-Strauss syndrome
Vasculitic disorder as opposed to an allergic condition.Often includes sinusitis as a clinical manifestation, whereas sinusitis rarely occurs with ABPA. [44] [45] [46]The skin and cardiovascular, GI, and nervous systems may also be involved. Skin symptoms include palpable purpura, petechiae, or granulomatous nodules. Cardiovascular symptoms include pericarditis, heart failure, and myocardial infarct. GI symptoms include diarrhoea, pain, bleeding, and colitis.
CXR: commonly shows transient and patchy opacities without lobar or segmental distribution. [46]Lung biopsy: eosinophilic infiltrates, an eosinophilic vasculitis (especially of the small arteries and veins), interstitial and perivascular necrotising granulomas, and areas of necrosis. [45] [46]
Hypereosinophilic syndromes (HES)
HES are associated with marked peripheral eosinophilia and potential involvement of diverse organs such as the heart, GI tract, lungs, brain, and skin. [47]Although 40% of HES patients have pulmonary manifestations, they also have signs and/or symptoms of end-organ dysfunction (not limited to the respiratory tract). Cardiac manifestations of eosinophilic myocarditis are the major cause of morbidity and mortality. Neurological manifestations of cerebral thromboemboli, encephalopathy, and neuropathy may be presenting symptoms. Colitis and gastritis may occur from eosinophil infiltration of gut mucosa. Common skin manifestations are eczema, hives, and angio-oedema.
Molecular testing for the FIP1L1/PDGFR-alpha mutation: may be positive for a genetic variant of HES. [48]Bone marrow evaluation: demonstrates increased eosinophils and eosinophil precursors or may confirm a myeloproliferative process. [47]Blood eosinophilia: HES has ≥1.50 x 10^9/L ( ≥1500/microlitre) present on at least 2 occasions in the absence of any other cause. In ABPA the cause is hypersensitivity to the Aspergillus mould, whereas in HES no aetiology is found.

Allergic rhinitis

non-allergic rhinitis
Sporadic or persistent perennial symptoms not resulting from IgE-mediated immunopathological events.Nasal congestion, pain/pressure, and a post-nasal drip sensation are common.Presence of nasal itching and sneezing less likely.Not common in children. Onset of symptoms after age 20 years more likely. [22]
Other than the absence of positive allergy tests, no single, specific differentiating feature exists.
acute sinusitis
Acute (<2 weeks), sub-acute (2-6 weeks).Acute disease often due to an infectious cause.Usually clinically diagnosed and may present with nasal congestion, cough, discoloured nasal mucus, and facial pressure/pain. [23]
Diagnosis is clinical.
chronic sinusitis
Symptoms >12 weeks. Usually diagnosed with the aid of radiological studies. One of the more common clinical characteristics of chronic sinusitis is the presence of hyposmia or anosmia.More commonly characterised by chronic inflammation than a bacterial infection, especially in adults. [23]
Sinus CT scans are abnormal, by definition, in sufferers of chronic sinusitis.
viral rhinosinusitis
Acute (<2 weeks) episode of rhinitis presenting with nasal congestion, rhinorrhea, sneezing, and varying degrees of nasal pruritus. May present with a sore throat, myalgias, headaches, discoloured mucus, and fever. More common during the autumn to spring months.
Diagnosis is usually clinical.

ALL High Risk Pre B cell Rapid Early responder (RER)

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

ALL High Risk Pre B cell Slow Early responder (RER)

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Alopecia areata

Trichotillomania
Patients with trichotillomania (compulsive hair pulling) may have other signs or symptoms of psychiatric/obsessive compulsive disorder. Nail-biting behaviour may be associated. [16]Odd or geometrical patterns of hair loss or a Friar Tuck pattern of hair loss with broken or blunt-tip hairs are seen.
Scalp biopsy shows melanin casts and trichomalacia. [17]
Tinea capitis
Tinea capitis occurs most commonly in children.The scalp is typically itchy, inflamed, and scaly; less commonly there is kerion formation with boggy areas of scalp.Lymph nodes are enlarged and tender.
Scalp biopsy shows hyphae on fungal stain.Fungal culture is positive.
Telogen effluvium
Alopecia is diffuse.There may be a history of a causative stressor (high fever, surgery, delivery) often at least 3 months before the onset of hair shedding.
Biopsy shows increased number of telogen follicles.
Syphilitic alopecia
There is a moth-eaten appearance of hair loss.
Rapid plasma reagin (RPR) and fluorescent treponemal antibody absorption test (FTA-ABS) are positive.
Systemic lupus erythematosus (SLE)
Alopecia is diffuse.
Anti-nuclear antibody (ANA) is positive.
Scarring alopecias
Lack of follicular ostia with various degrees of associated inflammation, scale, and erythema depending on the sub-type of scarring alopecia.
Biopsy findings either show a lymphocyte-predominant, neutrophilic-predominant or mixed inflammatory infiltrate (depending on the subtype of scarring alopecia) associated with destruction of hair follicles replaced by scarring.

Alpha-1 antitrypsin deficiency

Asthma
Clinically indistinguishable.
Pre-and post-bronchodilator spirometry: reversibility of obstruction is moderate in AAT deficiency emphysema, while obstruction is usually fully reversible in asthma.
COPD
Long periods of cigarette smoking, advanced age.
Obstructive, non-reversible pattern on spirometry, predominantly upper lobe changes on CXR/CT.
Bronchiectasis
Copious daily mucopurulent sputum, history of cystic fibrosis, history of primary ciliary dyskinesia, history of immunodeficiency, history of congenital disorders of the bronchial airways (e.g., Young's syndrome, Mounier-Kuhn syndrome, Williams-Campbell syndrome, pulmonary sequestration, yellow nail syndrome).
Marked dilation of airways on CT.Tests for possible causes may demonstrate the CFTR gene or ciliary dysfunction on biopsy.
Viral hepatitis
Positive for risk factors (e.g., blood transfusion, intravenous drug use, overseas travel).
Viral hepatitis serology including hepatitis A, B, and C antibodies.
Alcoholic liver disease
History of excess alcohol consumption, withdrawal symptoms when off alcohol, alcohol tolerance.
Reduced carbohydrate-deficient transferring (CDT), altered gamma-GT, AST, and ALT.

Alpha-thalassaemia

Iron deficiency anaemia
Symptoms associated with severe iron deficiency and not seen in alpha-thalassaemia include pica (the craving for non-food items).
Iron indices in alpha-thalassaemia will be consistent with iron-deficiency anaemia (low serum iron, high transferrin, low transferrin saturation, and low ferritin). Iron deficiency will also present as a microcytic, hypochromic anaemia; however, it will typically present as an acquired rather than a congenital disorder.RBC count will be high in alpha-thalassaemia and tend to be low or normal in iron-deficiency anaemia.If the diagnosis is in question, a short well-monitored trial of iron repletion will frequently confirm the diagnosis.
Beta-thalassaemia
Beta-thalassaemia major often presents at a few months of age with progressive pallor and abdominal distension; perinatal history is most often uneventful.
Beta-thalassaemia, with impaired beta-globin chain synthesis, will also present as a microcytic, hypochromic anaemia.Hb electrophoresis/HPLC will reveal an increased Hb A2 in most forms of beta-thalassaemia. Beta-globin gene sequencing will detect most but not all underlying molecular defects in beta-thalassaemia. Sequencing will not detect deletional beta-thalassaemias.
Variant haemoglobins (Hb E, Hb Lepore)
Patients with variant haemoglobin disorders have clinical manifestations of variable severity. When inherited in combination with beta(0)-thalassaemia, patients can present as beta-thalassaemia major.
Variant haemoglobins, either alone or in combination with other globin diseases, can present as a microcytic, hypochromic anaemia.Many of these will be detected by Hb electrophoresis/HPLC; however, DNA-based globin gene testing may be required to confirm the diagnosis.
Anaemia of chronic disease
Clinical history is crucial in differentiating anaemia of chronic disease from thalassaemia. History includes age of onset, family history, ethnicity of patient, prior haemoglobin and red cell indices, history of acute and chronic infections, autoimmune disorders, malignant disease, major trauma and surgery, and critical illness, with physical findings of the underlying disorder.
Degree of anaemia is typically mild to moderate and normocytic. Anaemia of chronic disease can uncommonly present as a microcytic, hypochromic anaemia.WBC and differential and platelet count may be elevated due to associated infection or inflammation.
Lead poisoning
Appropriate history of exposure to lead; irritability, aggressive behaviour, low appetite, difficulty sleeping, headaches, reduced sensations, loss of previous developmental skills, constipation; rarely, vomiting, muscle weakness, seizures, or coma.
Lead poisoning interferes with the enzyme ALA dehydratase and thus with haeme synthesis, and can lead to a microcytic anaemia.Peripheral smear will show basophilic stippling in lead poisoning, and the reticulocyte count will be depressed, in contrast to an elevated reticulocyte count in alpha-thalassaemia. Diagnosis can be confirmed by serum lead levels.
Sideroblastic anaemias (SA)
SA are due to defective haeme synthesis and can be congenital (i.e., X-linked) or acquired (lead, ethanol).History appropriate to acquired SA, including nutritional imbalances and prolonged exposure to toxins and drugs.History of myelodysplasia syndrome.
Two populations of red cells may be seen on peripheral smear in SA. Diagnosis is confirmed by bone marrow aspiration and biopsy.
B12 deficiency anaemia
Although anaemia due to B12 deficiency is classically easily distinguishable from thalassaemia by the high MCV and peripheral smear findings, B12 deficiency can also present as a normo-disorder or a microcytic disorder, often in the presence of co-existing iron deficiency. [36]B12 deficiency may also lead to neurological deficits: classically, a symmetrical neuropathy with ataxia associated with loss of position and vibration sense. [37] Other neurological findings include memory loss, irritability, and dementia.
The peripheral smear classically reveals hyper-segmented neutrophils and macrocytosis. Serum B12 level is low, and serum homocysteine and methylmalonic acid levels are elevated.Bone marrow examination, if performed, will reveal hypercellularity and megaloblastic changes. The anaemia will correct with vitamin B12 repletion.
Folate deficiency
Anaemia due to folate deficiency will also typically be macrocytic.
The MCV will be high, and serum homocysteine (but not methylmalonic acid) will be elevated. Serum and RBC folate levels will be low.
Other haemolytic anaemias
The patient who presents with anaemia must always receive a full diagnostic evaluation. The differential diagnosis includes other causes of haemolytic anaemia.
Active haemolysis will lead to an elevated LDH, low haptoglobin, indirect bilirubinaemia, and an elevated reticulocyte count. The evaluation must include investigation for both intra-corpuscular (enzyme and membrane defects) and extra-corpuscular (auto-immune mediated haemolytic anaemia, drug-induced haemolysis, or micro-angiopathic causes) aetiologies of haemolysis.
Haematological malignancies
The differential diagnosis of anaemia also includes haematological malignancies. Clues to the presence of an underlying malignancy include systemic symptoms (fever, weight loss), lymphadenopathy, and abnormalities in other cell lines with associated symptoms (i.e., thrombocytopenia and bleeding).
The white cell and platelet counts will frequently be abnormal. The peripheral smear may reveal evidence of the underlying disorder: for example, dysplasia in myelodysplastic syndrome and circulating blasts in acute myeloid or lymphoid leukaemia. An urgent bone marrow aspirate and biopsy are required to confirm the diagnosis.

Alport's syndrome

MYH9 disorders (Epstein's syndrome and Fechtner's syndrome)
Hx of easy bruising and bleeding. FHx may suggest autosomal-dominant inheritance. [23]
FBC reveals macro-thrombocytopenia. Due to mutations in the MYH9 gene. [23] [24]
Branchio-oto-renal syndrome
Autosomal-dominant disorder characterised by hearing loss; structural defects of the outer, middle, and inner ear; branchial fistulas or cysts; and renal disease. The condition shows reduced penetrance and variable expressivity, making diagnosis in some cases difficult.
Hearing loss may be sensorineural, conductive, or mixed on formal testing. Renal abnormalities ranging from mild hypoplasia to complete absence may be seen on ultrasound. Mainly due to mutations in the EYA1 and SIX1 genes. [25]
Thin basement membrane nephropathy
Usually no FHx of renal failure except in consanguineous families. Rarely associated with other types of glomerulonephritis. Hx is negative except for persistent microscopic haematuria.
All tests normal except for presence of haematuria of glomerular origin. Thin glomerular basement membrane on electron microscopy and normal immunohistochemical staining for type IV collagens in skin and kidney. COL4A3 and COL4A4 testing is available.
Familial focal segmental glomerulosclerosis
Usually no FHx of hearing loss and most likely autosomal dominant or recessive. No microscopic haematuria.
Diagnosis on renal biopsy. Mutations described in INF2, ACTN4, TRPC6, CD2AP, NPHS1, NPHS2, and PLCE1 have been identified, though it is highly genetically heterogeneous.
Maternally inherited diabetes and deafness
Maternally inherited and associated with a FHx of diabetes.
Mutation screening for mutations in MTTL1, MTTE, and MTTK.
IgA nephropathy
Usually no FHx. Absence of haematuria in relatives, although rare familial cases have been reported. No other associated features.
Renal biopsy reveals glomerular deposition of IgA.

Alzheimer's dementia

Mild cognitive impairment (MCI)
State of mild memory decline without loss of social or occupational functioning.10% of individuals diagnosed with MCI will progress to AD each year.
Mild memory complaints identified by history or through cognitive screening.Cognitive impairment not severe enough to meet full Diagnostic and Statistical Manual (DAM)-IV criteria for AD supports the diagnosis of MCI.
Delirium
Inattention and fluctuating level of consciousness.Disorientation common.Reversible causes may be present and should be corrected.Fluctuating course, worse at night-time.Fragmentary, fleeting hallucinatory experiences; visual, tactile, or auditory in form.
The Confusion Assessment Method (CAM) screening tool is well validated in distinguishing dementia.Repeated Mini-Mental State Examination (MMSE) or CAM evaluations will show acute fluctuations over time.
Depression
Hallmark features are depressed mood and loss of interest/pleasure in usual activities.Memory loss is not the predominant or a common feature.Depression may present acutely.Negative cognitions, preserved visuo-spatial function, and biological symptoms may help to differentiate.
Geriatric Depression Scale (long and short form), Hamilton Depression Scale, and Cornell Scale for Depression in Dementia may help to differentiate.Limited or no changes on MRI scanning.
Vascular dementia
Deficits include memory loss, emotional liability, Parkinsonism, and focal neurological deficits consistent with stroke location.Cardiovascular risk factors may be present.Further cognitive and functional decline occurs in a stepwise manner.Subcortical depression and apathy are common.
CT or MRI scanning demonstrates areas of past infarction and perivascular ischaemia.
Dementia with Lewy bodies
Vivid visual hallucinations, autonomic instability, and Parkinson's features (shuffling gait, bradykinesia, and falls) are characteristic.Rapid eye movement (REM) sleep disorder may be present.Progression of disease is more rapid than AD.
No reliable or valid differentiating test.Brain pathology demonstrates the presence of round, eosinophilic, intraneuronal inclusions called Lewy bodies. Neuropathological findings include neurofibrillary tangles, amyloid plaques, and Lewy neurites.
Frontotemporal dementia
Impulsive, socially inappropriate, and emotionally labile behaviour.Personality change and behavioural disturbance occur early and are prominent features.Verbal and language skills are blunted.Apathy and self-neglect are common.Onset often in 50s, progressing more rapidly than AD.
CT or brain MRI reveals structural atrophy in the frontal and/or temporal lobes.PET or single-photon emission computed tomography (SPECT) scanning shows reduced brain activity in the frontal and temporal lobes.Brain histology may reveal diagnostic findings (such as Pick bodies composed of tau protein, TDP-43 proteinopathy, or FUS proteinopathy).
Parkinson's disease dementia (PDD)
Features are similar to dementia with Lewy bodies (DLB) and include visual hallucinations, paranoia, and autonomic dysfunction.Motor symptoms include rigidity, resting tremor, bradykinesia, and postural instability preceding cognitive symptoms.
MRI usually reveals global brain atrophy in patients with PD.
Creutzfeld-Jacob disease (CJD)
Rapid decline in cognition or behaviour over several months in sporadic form; longer in variant form.Prominent psychiatric/behavioural symptoms in variant form (early onset, found mainly in UK and Europe).Marked impairment in executive functioning. Early neurological signs include startling myoclonus and paraesthesias, progressing to incontinence of faeces and urine, plus loss of speech.
Sporadic form: signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and fluid-attenuated inversion-recovery MRI often present. Cortical ribboning is also a common feature on these imaging sequences.Pulvinar sign in variant CJD (vCJD) is a common MRI finding.Tonsillar biopsy may be future diagnostic development in vCJD.Characteristic EEG findings are triphasic periodic sharp wave complexes seen on repeated EEG testing.CSF 14-3-3 protein essays are recommended to aid in diagnosis when the clinical suspicion is high.

Amblyopia

Refractive error with no amblyopia
Many refractive errors, most often myopia and astigmatism, cause unilateral or bilateral decreased vision but do not cause amblyopia. If a child's visual acuity immediately normalises with the appropriate refractive correction, the cause of decreased vision is refractive error alone, and not refractive amblyopia.Children with refractive error may squint to create a pinhole effect and improve vision, and myopic children will see better at near than at distance.In amblyopia, vision does not improve with squinting, nor does it improve at a particular testing distance.
Complete examination by an ophthalmologist (or optometrist).
Functional visual impairment
Typically presents with bilateral decreased visual acuity at a time when a child experiences stress, such as the birth of a new sibling, divorce, or loss of a loved one.A child with functional visual impairment will not show amblyogenic risk factors such as strabismus, significant refractive error, or media opacities, and the child should have an otherwise normal ophthalmological exam.
Complete examination by an ophthalmologist (or optometrist).
CNS pathology affecting visual pathways
Abnormal colour vision and visual field defects.
Complete examination by an ophthalmologist (or optometrist), brain and orbital MRI with gadolinium enhancement.

Amfetamine abuse

Cocaine abuse
Signs and symptoms are similar but shorter in duration.Half-life of cocaine is about 1 hour, but that of methamfetamine is 12 hours.
Confirmation with gas chromatography and mass spectroscopy (GC/MS) analysis. Considered the most specific and sensitive test. Will determine the exact compounds and presence of metabolites.A number of compounds (trazodone, ranitidine, ritodrine, chlorpromazine, and promethazine) can give false-positive results for methamfetamine with screening assays such as enzyme-multiplied immunoassay. Mebeverine, doxepin, and its metabolite n-desmethyldoxepin can cause false-positive results if a fluorescence polarisation assay is used. GC/MS does not have this problem.Some drugs are metabolised to amfetamines. Selegiline is metabolised to L-amfetamine and L-methamfetamine and causes a false-positive GC/MS result. Quantitative isomer analysis can distinguish the L from R isomer. Clobenzorex, an anorectic medication from Mexico, is metabolised to D-amfetamine, giving positive screening, GC/MS confirmation, and qualitative isomer analysis.
Malignant HTN
Usually a history of HTN and a lack of CNS stimulation, which is common in amfetamine toxicity.
A negative urine toxicology test differentiates a hypertensive crisis from a drug-abuse symptom.
Anticholinergic drug exposure
History of ingestion with absent or decreased bowel sounds and dry mucous membranes, not present with amfetamine use.
A negative urine toxicology screen with a positive screen for anticholinergics provides differentiation.A positive response to the cholinesterase inhibitor physostigmine test suggests anticholinergic drug use.
Neuroleptic malignant syndrome
May be a history of neuroleptic exposure.May respond to bromocriptine.
Urine toxicology screen is negative for amfetamines, unless there is concomitant amfetamine use.
Malignant hyperthermia
History of recent general anaesthesia or receipt of muscle blockers.May be FHx of similar episodes.Responds to dantrolene sodium.
Urine toxicology screen is negative for amfetamines, unless there is concomitant amfetamine use.
Phaeochromocytoma
Paroxysmal symptoms without a history of drug abuse.
Characterised by recurrent hypertensive episodes with negative urine toxicology screens.Suggested by marked elevation of unconjugated catecholamines, metanephrines, and vanillylmandelic acid in the 24-hour urine collection test.
Schizophrenia
History of psychiatric illness and previous neuroleptic treatment without drug abuse.
Urine toxicology screen is negative for amfetamines, unless there is concomitant amfetamine use.
Depression
History of previous episodes of depression often with previous antidepressant therapy.
Urine toxicology screen for amfetamines is negative, unless there is concomitant amfetamine use.
Paranoid schizophrenia
History of previous psychiatric illness without drug abuse.
Urine toxicology for amfetamines is negative, unless there is concomitant amfetamine use.

Amfetamine overdose

Cocaine overdose
Toxicity from amfetamines cannot be readily distinguished clinically from cocaine toxicity, but the management in both cases is essentially the same. The prevalence of ischaemic chest pain and CVA in cocaine intoxication is higher.
Urine drug screen will differentiate cocaine from amfetamines.
Serotonin syndrome
Hx of drug use, prescription or illicit, with proclivity to serotonin interaction (e.g., serotonin-reuptake inhibitors, metoclopramide, sumatriptan, lithium, and dextromethorphan). Anxiety, agitation, delirium, restlessness, and disorientation; bilateral Babinski's signs; neuromuscular findings are typically more pronounced in the lower extremities.
Non-specific laboratory findings, including an elevated WBC count, elevated creatine kinase, and decreased serum bicarbonate concentration. Level for suspected agent causing interaction (if available) may be diagnostic.
Withdrawal of gamma-hydroxybutyrate or its analogues
Gamma-hydroxybutyrate (GHB) is an illicit chemical that has become a major cause of drug-related comas in the US and other countries. GHB withdrawal tends to cause mild autonomic dysfunction with severe CNS symptoms. [44]
GHB and its analogues are not detected on standard drug screens and are rapidly cleared from the urine (75-100 mg/kg may be undetectable in the urine by 12 hours after administration). [44] [45] May require process of elimination of known illicit drug usage.
Psychosis
May be drug-induced or exacerbation of pre-existing condition and difficult to discern exactly, but differentiating these is not a contra-indication to urgent sedation and symptomatic therapy.
A period of sedation and behavioural control followed by a more extensive history will allow reassessment after the acute drug effects have worn off.
Alcoholism
Commonplace, chronic in nature, malnutrition, hepatomegaly, jaundice, and ascites.
Carbohydrate-deficient transferrin confirms diagnosis but is not widely available. Serum alcohol >22,440 micromol/L (200 mg/dL) with limited impairment can indicate tolerance to the effects of alcohol but does not diagnose dependence.
Hypoglycaemia
Hx of diabetes and insulin therapy, or oral hypoglycaemic agents.
Documentation of blood glucose <3.3 mmol/L (60 mg/dL) with accompanying symptoms is crucial to diagnosing clinically significant hypoglycaemia.
Sedative or hypnotic withdrawal
Hx of prolonged use or high doses, discontinued in the previous 1 to 6 days. Hyperthermia not a prominent feature. Older people more at risk. Usually a longer period of onset.
Toxicology screening may identify the agent.
Antimuscarinic syndrome
Rather than the diaphoresis of amfetamine toxicity, a patient with antimuscarinic syndrome has dry mucosal membranes and hot, red, and dry skin. Older men are likely to have urinary retention. Voluntary admission of ingestion of anticholinergic agents, antihistamines, antispasmodic agents, some antidepressants (especially tricyclic antidepressants), ophthalmic cycloplegics, or some plant derivatives including belladonna and Datura species.
Toxicology screening may identify the agent.
Alcohol withdrawal
Hx of chronically high alcohol intake followed by abrupt withdrawal may be elicited. Hypertension, tachycardia, and agitation become more severe within hours to several days.
Toxicology screening may identify the agent. Other indicators are high gamma-GT on liver function tests and macrocytosis on FBC.
Heat stroke
Hx of exposure to extreme heat, especially with physical exertion; hot, flushed, and dry skin; variable amounts of sweating may occur, but usually less than expected with amfetamine toxicity. Prostration, exhaustion much more common than agitation and rage.
Concentrated urine, haemoconcentration with decreased coagulation, and thrombocytopenia. Elevated WBC count and core body temperature, usually negative drug and alcohol screens.
Subarachnoid haemorrhage
Sudden severe headache, often described as worst headache of life, with nausea, vomiting, and photophobia, meningismus, intra-ocular haemorrhages, or focal findings.
Subarachnoid haemorrhage identifiable on CT or MRI. LP with blood may indicate cerebral bleeding or traumatic spinal tap. Cerebral angiography confirms the presence of aneurysms.
Phaeochromocytoma
Hx of similar attacks with headache in the absence of drug abuse.
Urinary catecholamines are elevated, or elevated metanephrines, with normal serum T4.
Thyrotoxic crisis
Hx of thyrotoxicosis in the past, may be precipitated by amfetamine or other sympathomimetic ingestion.
Elevated levels of T3, T4 and free T4, hyperglycaemia, leukocytosis, and anaemia.
Encephalitis
Fever, headache, lethargy, and altered mental status; immunocompromised state, motor and sensory deficits, or focal neurological findings; seizures.
CT head (non-contrast) normal or subtly abnormal, hypodense lesions, and mild mass effect prominent later; CSF for cell count and for Gram stain, bacterial culture diagnostic with identification of organism.
Meningitis
Headache, lethargy, and altered mental status; immunocompromised state, fever, meningismus, and lethargy, seizures.
CT head (non-contrast) normal; CSF for Gram stain, bacterial culture diagnostic with identification and recovery of organism.

AML Protocol (MRC 12)

Acute lymphocytic leukaemia
Clinically indistinguishable from AML.
Bone marrow biopsy, peripheral blood smear, immunophenotyping, and immunochemistry may be helpful in establishing the diagnosis.Blast cells are positive for deoxynucleotidyl transferase and lack staining for myeloperoxidase; also demonstrate presence of lymphoid markers.
Biphenotypic leukaemia
Palpable lymph nodes may be present.
The expression of antigens representing both the myeloid and lymphoid leukaemia in the leukaemic clone suggests biphenotypic leukaemia. Cytogenetics may show Philadelphia chromosome t(9:22).
Myelodysplastic syndrome
History of long-standing anaemia and transfusion dependence.
The distinction between high-risk myelodysplastic syndrome (MDS) and AML is artificial in that it is based on the numbers of blasts present. The estimation of blast counts can be difficult and is subjective. The blood film shows dysplasia in >10% of cells of any lineage and the bone marrow may show up to 19% blasts.Micromegakaryocytes and acquired Pelger-Huet (spectacle eye nucleus) neutrophils are specific for MDS. Associated chromosomal deletions or unbalanced chromosomal abnormalities, particularly of chromosomes 8, 7, and 5, are common. Complex cytogenetic changes may occur.The presence of dysplasia may suggest that AML has evolved from MDS.
Chronic myelogenous leukaemia blast crisis
There may be a history of preceding chronic myelogenous leukaemia (CML).
The peripheral blood film may be indistinguishable from AML but may have an excess of basophils and eosinophils.The presence of the Philadelphia chromosome t(9:22) (q34;q11) supports a diagnosis of CML but does not exclude Philadelphia chromosome-positive AML.Typically no other karyotypic abnormalities are present.
Myelofibrosis
Typically splenomegaly is present.
Blood film shows teardrop RBCs and a leukoerythroblastic film.Bone marrow biopsy shows reticulin fibrosis.
Aplastic anaemia
May have history of medications that cause aplastic anaemia, such as chloramphenicol and non-steroidal anti-inflammatory drugs.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Low percentage of blast cells in peripheral blood (<10%). Precursors are morphologically normal.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.Patients should also be evaluated for an underlying paroxysmal nocturnal haemoglobinuria and evidence of intravascular haemolysis (reticulocytosis, elevated serum lactate dehydrogenase, and indirect bilirubin, and decreased haptoglobin). A negative Coombs test is suggestive.
Drug-induced bone marrow failure
History of using medications that may cause pancytopenia such as chloramphenicol, methotrexate, and chemotherapeutic agents.Cessation of the implicated agent or administration of an antidote such as folic acid for methotrexate reverses the pancytopenia.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow will be hypocellular, and no excess of blasts are present.Megaloblastic erythropoiesis is seen with methotrexate.Bone marrow should be reassessed after holding medication.
Leukaemoid reaction
Recent history of haematopoietic growth factor treatment may be present.Appropriate treatment (i.e., stopping the growth factor) results in normalisation of the blood count.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow shows no excess of blasts but mature haematopoietic cells. Increased macrophage activity and toxic granulation of myeloid cell series may be present suggesting infections; Dohle bodies may also be seen in infections.
Vitamin B12 deficiency
May have a family history consistent with pernicious anaemia.Paresthesia is an early symptom.Glossitis and neurological signs, such as cognitive impairment or subacute combined degeneration (ataxia, decreased vibration sense, muscle weakness, and hyporeflexia), occur with severe deficiency.
Macrocytic anaemia will be present unless there is an associated iron deficiency.Peripheral blood smear shows megaloblastic changes.Serum vitamin B12 levels are low.

Amoebiasis

Infectious diarrhoea
Differential diagnosis is broad as various bacteria, parasites, and viruses cause diarrhoea.
Presence of specific infectious agent on stool or serological testing.
Ulcerative colitis
Absence of history of travel to endemic areas.Bloody diarrhoea.
Stool and antigen testing negative for infectious agents.Typical colonoscopy and biopsy appearance.
Pyogenic liver abscess
Occurs predominantly in females.Jaundice is more common with pyogenic liver abscess than with amoebic liver abscess.Associated with hepatobiliary disease.
Infective organism identified in blood or pus culture.
Necrotic hepatoma
Absence of history of travel to endemic areas or diarrhoea.
Aspirate of hepatoma negative for infectious cause.
Fascioliasis (liver flukes)
There are no physical differentiating characteristics.
Key diagnostic test is positive serum antibody for fascioliasis.Eosinophilia.
Echinococcal liver cyst
There are no physical differentiating characteristics.
Positive serum antibody test for echinococcus.Aspiration of cyst should be avoided because of the possibility of anaphylaxis.

Amyloidosis

Hypertrophic cardiomyopathy (HCM)
Clinically difficult to distinguish HCM from amyloidosis.
Echo meets diagnostic criteria for HCM, such as asymmetric septal hypertrophy.Doppler echo with strain to exclude features of amyloidosis does not show the typical restrictive filling changes seen in amyloidosis.MRI can help distinguish between the 2 syndromes.
Membranous glomerulopathy
Clinically similar presentation in patients who present with nephrotic syndrome.
Renal biopsy does not stain with Congo red.
Monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy
Patients do not have significant degrees of proteinuria, hepatomegaly, or cardiomyopathy.
Sural nerve biopsy does not stain with Congo red.
Multiple myeloma
Bone pain and symptoms of anaemia and renal failure.
Plain x-rays show lytic bone lesions, compression fractures, diffuse osteoporosis.Low Hb.Renal impairment.

Amyotrophic lateral sclerosis

Cervical spondylosis with myelopathy and radiculopathy
Presents with LMN signs at lesion level and UMN signs below the lesion level.Usually has associated sensory symptoms and bladder and bowel disturbances.
MRI cervical spine shows cord compression and multiple spinal root compressions.
Multifocal motor neuropathy
Presents with LMN-only signs, involving 1 or both upper extremities.Might begin with severe weakness in a limb without significant atrophy, with atrophy occurring later in the disease course. [43]
Electrodiagnostic studies: multifocal nerve conduction block (with other locations than the usual entrapment sites). High GM1 ganglioside antibody titre (up to 80% of patients). [42]
Inclusion body myositis
Slowly progressive.Weakness affecting mainly the finger flexors and thigh flexors.There are no UMN signs.
Electromyography: evidence for myopathy.Clinical examination should not show UMN signs.
Monomelic amyotrophy
Focal, predominantly LMN signs and symptoms, with usual occurrence in young people.Commonly involves an upper extremity.Severity of symptoms may progress over a few years while remaining limited to the initially involved limb. [44]More frequent in Indian and Japanese populations.
Clinical evaluation distinguishes this entity from ALS.
Myasthenia gravis
Symptoms fluctuate.Ocular symptoms (ptosis, diplopia, extra-ocular muscle dysfunction) are possible.UMN/LMN signs are absent.Can mimic bulbar-onset ALS, if presents with dysphagia, dysarthria, or facial diplegia.Weak but otherwise normal tongue in electromyography (EMG).
Acetylcholine receptor antibodies present.Tensilon test shows improvement in weakness with acetylcholinesterase inhibitors.Repetitive nerve stimulation may be abnormal in both conditions, but in ALS, the EMG of tongue and facial muscles shows ongoing and chronic denervation.
Benign fasciculations
Focal or diffuse fasciculations, without other neurological symptoms or signs. [45]
Electromyography shows only simple fasciculations, without any motor unit potential abnormalities.
Post-polio syndrome
Only LMN symptoms.Slow progressive course.Occurs in the segments initially involved by polio a long time after the initial viral disease. [46]
Clinical evaluation distinguishes this entity from ALS.
Primary lateral sclerosis
Initially an isolated UMN disorder.Most patients may develop LMN features in time, converting into an UMN-dominant ALS.Slowly progressive weakness with associated spasticity.Progresses at a slower pace when compared with ALS. [1] [2]
Serial clinical evaluation provides data for diagnosis. EMG excludes the LMN signs.
Progressive muscular atrophy
Isolated LMN disorder.Progressive weakness, atrophy, and fasciculation.Some patients develop UMN symptoms and signs later during the disease course, converting into LMN-dominant ALS. [1]
Serial clinical evaluations used for diagnosis.

AM L (M3)

Acute lymphocytic leukaemia
Clinically indistinguishable from AML.
Bone marrow biopsy, peripheral blood smear, immunophenotyping, and immunochemistry may be helpful in establishing the diagnosis.Blast cells are positive for deoxynucleotidyl transferase and lack staining for myeloperoxidase; also demonstrate presence of lymphoid markers.
Biphenotypic leukaemia
Palpable lymph nodes may be present.
The expression of antigens representing both the myeloid and lymphoid leukaemia in the leukaemic clone suggests biphenotypic leukaemia. Cytogenetics may show Philadelphia chromosome t(9:22).
Myelodysplastic syndrome
History of long-standing anaemia and transfusion dependence.
The distinction between high-risk myelodysplastic syndrome (MDS) and AML is artificial in that it is based on the numbers of blasts present. The estimation of blast counts can be difficult and is subjective. The blood film shows dysplasia in >10% of cells of any lineage and the bone marrow may show up to 19% blasts.Micromegakaryocytes and acquired Pelger-Huet (spectacle eye nucleus) neutrophils are specific for MDS. Associated chromosomal deletions or unbalanced chromosomal abnormalities, particularly of chromosomes 8, 7, and 5, are common. Complex cytogenetic changes may occur.The presence of dysplasia may suggest that AML has evolved from MDS.
Chronic myelogenous leukaemia blast crisis
There may be a history of preceding chronic myelogenous leukaemia (CML).
The peripheral blood film may be indistinguishable from AML but may have an excess of basophils and eosinophils.The presence of the Philadelphia chromosome t(9:22) (q34;q11) supports a diagnosis of CML but does not exclude Philadelphia chromosome-positive AML.Typically no other karyotypic abnormalities are present.
Myelofibrosis
Typically splenomegaly is present.
Blood film shows teardrop RBCs and a leukoerythroblastic film.Bone marrow biopsy shows reticulin fibrosis.
Aplastic anaemia
May have history of medications that cause aplastic anaemia, such as chloramphenicol and non-steroidal anti-inflammatory drugs.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Low percentage of blast cells in peripheral blood (<10%). Precursors are morphologically normal.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.Patients should also be evaluated for an underlying paroxysmal nocturnal haemoglobinuria and evidence of intravascular haemolysis (reticulocytosis, elevated serum lactate dehydrogenase, and indirect bilirubin, and decreased haptoglobin). A negative Coombs test is suggestive.
Drug-induced bone marrow failure
History of using medications that may cause pancytopenia such as chloramphenicol, methotrexate, and chemotherapeutic agents.Cessation of the implicated agent or administration of an antidote such as folic acid for methotrexate reverses the pancytopenia.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow will be hypocellular, and no excess of blasts are present.Megaloblastic erythropoiesis is seen with methotrexate.Bone marrow should be reassessed after holding medication.
Leukaemoid reaction
Recent history of haematopoietic growth factor treatment may be present.Appropriate treatment (i.e., stopping the growth factor) results in normalisation of the blood count.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow shows no excess of blasts but mature haematopoietic cells. Increased macrophage activity and toxic granulation of myeloid cell series may be present suggesting infections; Dohle bodies may also be seen in infections.
Vitamin B12 deficiency
May have a family history consistent with pernicious anaemia.Paresthesia is an early symptom.Glossitis and neurological signs, such as cognitive impairment or subacute combined degeneration (ataxia, decreased vibration sense, muscle weakness, and hyporeflexia), occur with severe deficiency.
Macrocytic anaemia will be present unless there is an associated iron deficiency.Peripheral blood smear shows megaloblastic changes.Serum vitamin B12 levels are low.

Anabolic steroid abuse

Ovarian cancer
No hx of taking anabolic steroids.Anorexia and weight loss.Lack of muscle bulking.
Negative urine test for anabolic steroids.Pelvic ultrasound shows presence of solid, complex, septated, multiloculated mass and high blood flow.CT scan shows peritoneal thickening, enlarged lymph nodes, ascites, omental thickening, or liver metastases.
Adrenal neoplasm
No hx of taking anabolic steroids.
Negative urine test for anabolic steroids.MRI of abdomen/pelvis typically appears hyper-intense to the liver on T2-weighted images because of their high water content.Appear on CT scan as inhomogeneous masses, often with a central area of low attenuation that represents haemorrhage or necrosis.
Congenital adrenal hyperplasia
Typically presents in infancy.No hx of taking anabolic steroids in patients with late-onset disease.
Negative urine test for anabolic steroids.Elevated serum 17-hydroxyprogesterone demonstrates deficiency of 21-hydroxylase.
Polycystic ovarian syndrome
No hx of taking anabolic steroids.Hyper-androgenism.Body is obese and pear shaped.
Negative urine test for anabolic steroids.Pelvic ultrasound shows polycystic ovaries.Glucose tolerance test shows insulin resistance.
Precocious puberty
No hx of taking anabolic steroids.Lack of masculinisation effects (ovarian and central precocious puberty).Lack of feminisation effects (testicular and central precocious puberty).
Negative urine test for anabolic steroids.Gonadotrophin-dependent precocious puberty tends to have both elevated LH and elevated FSH, both of which increase after taking exogenous GnRH.Gonadotrophin-independent precocious puberty patients have low levels of FSH and LH, and these hormones do not rise after GnRH dosing.
Anorexia nervosa
May co-exist with steroid abuse.No hx of taking anabolic steroids.Patients often believe they are overweight.Lack of muscle bulking.Low daily calorie count.
Negative urine test for anabolic steroids.
Cushing's syndrome
No hx of taking anabolic steroids.Hx of intake of glucocorticoids.
Negative urine test for anabolic steroids.Elevated serum cortisol level.High 24-hour urine cortisol excretion.Positive dexamethasone suppression test (persistently high cortisol after giving dexamethasone).
Drug-induced hirsutism
No hx of taking anabolic steroids.Hx of taking drugs known to cause hirsutism including minoxidil, phenytoin, danazol, or diazoxide.
Negative urine test for anabolic steroids.Gas chromatography/mass spectrometry detection of exogenous drugs may confirm diagnosis.
Drug-induced jaundice
No hx of taking anabolic steroids.Hx of taking drugs known to cause jaundice including oral contraceptives, ethanol, or isoniazid.
Negative urine test for anabolic steroids.Gas chromatography/mass spectrometry detection of exogenous drugs may confirm diagnosis.
Haemolytic anaemia
No hx of taking anabolic steroids.Symptoms develop rapidly.Tachycardia and pallor.
Negative urine test for anabolic steroids.Decreased haemoglobin level and haematocrit with high reticulocyte count.Increased serum bilirubin concentration.
Hepatitis
No hx of taking anabolic steroids.Hx of sharing needles, intercourse with infected partner, or travel exposure (viral hepatitis).Hx of taking drugs/toxins known to cause hepatitis including paracetamol, valproate, troglitazone, mushrooms, pennyroyal, or carbon tetrachloride (drug-induced hepatitis).
Negative urine test for anabolic steroids.Elevated indirect bilirubin.Positive hepatitis serology.Toxicology testing may detect drugs or other substances that induce hepatitis (drug-induced hepatitis).
Cirrhosis
No hx of taking anabolic steroids.Hx of chronic alcohol ingestion.Liver feels firm and nodular on examination.Ascites.Splenomegaly.Clubbing.Spider angiomata.
Negative urine test for anabolic steroids.Liver biopsy demonstrates architectural distortion of the liver parenchyma with formation of regenerative nodules.Prolonged prothrombin time and decreased platelet count.
Hepatic malignancy
No hx of taking anabolic steroids.Anorexia and weight loss.Lack of muscle bulking.
Negative urine test for anabolic steroids.Liver biopsy demonstrates malignancy.
Cholelithiasis
No hx of taking anabolic steroids.
Negative urine test for anabolic steroids.Gallstones occasionally seen on plain x-ray or CT, and reliably identified with ultrasound.
Abuse of other ergogenic compounds
Hx of taking alternative ergogenic compound; patients may also currently use, or have previously used, anabolic steroids. [38]Other ergogenic compounds include oestrogen-receptor blockers (e.g., tamoxifen, clomifene, raloxifene, toremifene, droloxifene), aromatase inhibitors (e.g., aminoglutethimide, testolactone, atamestane, exemestane, anastrozole, letrozole, vorozole), oestrogen precursors (e.g., dehydroepiandrosterone [DHEA], androstenedione), and the gonadotrophins (e.g., LH, hCG). [38]
Specific mass spectrometry testing is required to identify these compounds. [38]

Anaemia of chronic disease

Iron deficiency anaemia
Signs and symptoms of anaemia per se may be identical to ACD. Evidence of bleeding, or a compelling cause for poor iron absorption, may be found in iron deficiency, whereas these are absent in ACD.
Ferritin is typically low (<112 picomol/L (50 nanograms/mL)) in iron deficiency; normal or elevated (>225 picomol/L (100 nanograms/mL)) in ACD. A ferritin level <33 picomol/L (<15 nanograms/mL) strongly suggests iron deficiency. The transferrin saturation is typically <10% in iron deficiency; a value of <5% makes iron deficiency very likely.TIBC is typically elevated in iron deficiency anaemia (>70 micromol/L (400 micrograms/dL)) and reduced (<45 micromol/L (250 micrograms/dL)) in ACD.Soluble transferrin receptor (sTfR) is elevated in iron deficiency, normal in ACD. [7] The ratio of sTfR (mg/L) to log ferritin (micrograms/L) is >2 in iron deficiency.Bone marrow iron is absent in iron deficiency anaemia.
Iron deficiency anaemia co-existing with ACD
There may be no differentiating symptoms or signs.
Ferritin less helpful. Lowering the cutoff value from <225 picomol/L (<100 nanograms/mL) to <100 picomol/L (<45 nanograms/mL) increases the likelihood ratio of iron deficiency anaemia from 3.2 to 11.1. A ferritin of <33 picomol/L (<15 nanograms/mL) essentially rules in iron deficiency. [15]It is helpful to know that ferritin is approximately threefold elevated over baseline when inflammation is present. Thus, a ferritin of 100 picomol/L (45 nanograms/mL) in a patient with a recent known value of 33 picomol/L (15 nanograms/mL) would suggest co-existent ACD.
Anaemia associated with chronic renal disease (erythropoietin deficiency)
Symptoms and signs may be identical to ACD.Patient more likely to present with conditions related to chronic renal disease (e.g., diabetes, hypertension, polycystic kidney disease).Patients with end-stage renal disease, including those on dialysis, may have ACD in addition to anaemia of renal disease.
Serum creatinine is typically at least mildly elevated. Rarely, only the creatinine clearance is reduced, as in early diabetic chronic kidney disease.When ACD co-exists with anaemia of renal disease, ferritin (absent in iron deficiency) should be higher than otherwise, and CRP and ESR should be elevated.
B12 deficiency (e.g., pernicious anaemia)
Hx of diet poor in sources of vitamin B12, or heavy alcohol use.Posterior column symptoms and signs (e.g. ataxia, gait abnormalities) may be present.Occasionally may be other neurologic symptoms and signs (e.g. peripheral neuropathy).
Anaemia is typically macrocytic (MCV >100 fL).Serum B12 is low (<200 picograms/mL).
Folate deficiency
Hx of diet poor in sources of folate, or heavy alcohol use.
Anaemia is macrocytic (MCV >100 fL).Serum folate low (<2.5 nanograms/mL).RBC folate level <140 nanograms/mL.
Thalassemia
More likely to be a family hx of thalassemia.More common in certain ethnic groups (Mediterranean, south Asian, or east Asian ancestry).
MCV is low and MCHC is relatively normal in thalassemia trait, and haemoglobin A2 is increased.Blood smear shows microcytosis and significant poikilocytosis.
Anaemia due to drugs, radiation, and chemical exposure
Appropriate hx of exposure to radiation, chemicals, or medication, especially having recently started to take a drug known to cause anaemia.
Bone marrow examination may show incipient or fully developed aplastic anaemia.Absolute reticulocyte count is typically low for the degree of anaemia in hypoplastic and aplastic anaemia.
Primary haematological disorder (e.g., myelodysplasia, multiple myeloma, leukaemia, lymphoma)
Bone pain, hx of recent fracture, purpura, ecchymoses, lymphadenopathy, hepatomegaly, splenomegaly are all more likely with primary haematological disorder than in ACD.
MCV normal or mildly increased. FBC may show leukopenia, granulocytopenia, thrombocytopenia, leukocytosis, or thrombocytosis. Peripheral smear may show precursor cells. LDH may be increased.

Anal cancer

Haemorrhoids
Rectal pain and bleeding can occur with both haemorrhoids and anal cancer, and they are often difficult to distinguish on the basis of symptoms.Physical examination reveals no palpable mass with haemorrhoids.
Biopsy is negative for malignancy in haemorrhoids.
Rectal cancer
Difficult to distinguish on the basis of symptoms. Rectal cancer causes a rectal mass rather than an anal mass.
Colonoscopy to identify a mass in the rectum.
Anal margin cancer
Indistinguishable from anal canal cancer on the basis of symptoms. On physical examination, the tumour is located in the perianal skin and does not involve the anal verge.
No tests can differentiate anal margin cancer from anal cancer.

Anal fissure

Crohn's disease
History of Crohn's disease.Abnormal-looking perianal skin.Presence of anal fistulae, lateral site of fissure.Painless fissure (in 50%).
Evaluation under anaesthesia (EUA) and biopsy showing histopathological evidence of Crohn's disease.
Sarcoidosis
History of sarcoidosis.Lateral site of fissure.
CXR suspicious of sarcoid.EUA and biopsy showing histopathological evidence of sarcoid.
Tuberculosis
History of tuberculosis.Lateral site of fissure.
CXR suspicious of TB.EUA and biopsy showing histopathological evidence of TB; culture of tissue from fissure growing Bacterium tuberculosis.
HIV infection
History of HIV.High-risk behaviors in history.
Enzyme-linked immunosorbent assay (ELISA), western blot, RNA test, or DNA polymerase chain reaction (PCR) positive for HIV.
Lymphoma
Lymphadenopathy elsewhere.Night sweats.
Biopsy of enlarged lymph nodes.
Syphilis
Inhaling fissure.High-risk behaviours in history.
Serum tests positive for syphilis.
Anal carcinoma
History of human papillomavirus (HPV) infection.Atypical site and shape of fissure.
EUA and biopsy showing squamous cell carcinoma.

Anaphylaxis

Septic shock
Absence of previous allergic reactions, lack of allergen exposure, slower onset, fever, and other signs of localised infection often differentiate septic shock from anaphylaxis.
Increased WBC count and increased temperature.CXR with a pulmonary infiltrate is suggestive of underlying pneumonia as source of infection.
Cardiogenic shock
Age, risk factors for CAD, previous angina episodes, absence of an allergic history, no indication of allergen exposure, typical cardiac signs and symptoms (such as chest pain on exercise) help to distinguish. Severe anaphylactic reactions can trigger cardiac events.
Elevated cardiac enzymes (CK and troponin). ECG may show signs of myocardial ischaemia (elevated ST segments or flipped T waves). CXR may show signs of CHF (e.g., pulmonary oedema, changes in the cardiac silhouette).
Hypovolaemic shock
Water or fluid loss occurs via heat exposure, profuse sweating, significant blood loss, vomiting, and diarrhoea. Patients report thirst and a drop in urinary output. Anaphylaxis is a form of hypovolaemic shock secondary to intravascular fluid shifts. Establishing an alternative cause of hypovolaemia will differentiate from anaphylaxis.
A drop in haematocrit suggests blood loss.A serum urea/creatinine ratio >20 suggests volume depletion.
Vasovagal reaction
The characteristic feature is hypotension, with pallor, weakness, nausea, vomiting, and diaphoresis. The sudden onset, the cardiovascular collapse, and unconsciousness are all also typical of anaphylaxis.May be differentiated by the lack of cutaneous manifestations, the absent allergic history, and the presence of bradycardia instead of the tachycardia, even though either can be absent or misleading.
There is no differentiating test.
Asthma
Absence of allergen exposure, or of cutaneous or digestive findings, and a hx of previous asthma episodes help to differentiate. A rapid onset is suggestive of anaphylaxis and should at least trigger referral to higher-level medical care.
There is no differentiating test.
Acute COPD exacerbation
Absence of allergen exposure, or of cutaneous or digestive findings, and a hx of established chronic lung disease help to differentiate.
There is no differentiating test.
Hereditary angio-oedema
Characterised by recurrent episodes of slowly progressing angio-oedema of the skin, mucosa, and submucosal tissue. There is no urticaria, hypotension, or history of allergen exposure as in anaphylaxis. FHx is positive.
Deficiency or underactivity of the C1 esterase inhibitor enzyme.Serum complement C4 and CH50 are low.
Vocal cord dysfunction syndrome
Cutaneous signs, digestive findings, hypotension, and allergen exposure are not present.
Pharyngeal endoscopy by an ENT consultant will not show laryngeal oedema but instead vocal cord adduction.
Foreign body aspiration
No allergen exposure, no cutaneous or digestive findings, but a hx of foreign body aspiration differentiate this diagnosis.
Imaging and bronchoscopy are used to locate and document the foreign body. If the object inhaled is radio-opaque (e.g., a small coin), a plain radiograph of the chest may show its location.
Monosodium glutamate (MSG) ingestion
In reaction to MSG exposure, the following MSG symptom complex may occur. One or more of the following are present: burning sensation in the back of the neck, forearms, and chest; numbness in the back of the neck, radiating to the arms and back; tingling, warmth, and weakness in the face, temples, upper back, neck, and arms; facial pressure or tightness; chest pain; headache; nausea; rapid heartbeat; bronchospasm; drowsiness; and weakness. No urticaria, angio-oedema, or hypotension occurs.
Serum histamine levels and mast cell tryptase are not elevated.
Carcinoid syndrome
On examination, there is an associated right heart murmur.
Urinalysis will show high levels of hydroxy indole acetic acid.
Postmenopausal hot flushes
Flush appears several times a day and lasts for 4 to 5 minutes. There are no respiratory tract symptoms and no hypotension.
There is no differentiating test.
Red man syndrome
This syndrome usually appears within 4 to 10 minutes after start or soon after the completion of a vancomycin infusion. It is characterised by flushing and/or an erythematous rash that affects the face, neck, and upper torso. Hypotension and angio-oedema may also occur, but less frequently.
There is no differentiating test.
Panic disorder
In some, functional stridor develops as a result of forced adduction of the vocal cords; however, there is no urticaria, angio-oedema, or hypotension.
There is no differentiating test.
Scombrotoxic food poisoning
Symptoms resemble IgE-mediated food allergy, but most prominent on upper torso and face. Erythematous rash, but no urticaria noted. Resolves untreated within 12 hours.
Skin test to suspected seafood is negative. Histamine level in consumed fish elevated.

Anatomical penile abnormalities

Balanoposthitis
Inflammation of the glans penis without constrictive foreskin.
Clinical diagnosis.
Encircling foreign body
A foreign body wrapped around the penis (such as a hair or thread) can lead to distal swelling and oedema similar to paraphimosis.
Clinical diagnosis.
Trapped penis
A trapped penis is a buried penis due to scar tissue, typically from previous circumcision. This scar is usually palpable around the penis, rather than a smooth transition from pre-pubic to penile skin.
Clinical diagnosis.
Diminutive penis
A diminutive penis is a penis that seems small due to abnormality such as epispadias or hypospadias. Evident by an abnormally positioned urethral meatus.
Clinical diagnosis.
Webbed penis
A webbed penis is a buried penis due to skin webbing at the penoscrotal junction. A small bridge of tissue connecting the ventral proximal penis to the scrotum is palpable.
Clinical diagnosis.

Androgenic alopecia

Diffuse alopecia areata
This is a non-scarring, autoimmune, inflammatory hair loss, which is typically characterised by circumscribed and asymmetrical areas of baldness.The scalp is the most common site affected.Diagnosis is suggested by findings of short broken-off (exclamation-point) hairs, pitted nails and a history of periodic regrowth of hair. [19]
Histopathology of a scalp biopsy is characterised by an increased number of catagen and telogen follicles, and the presence of lymphocytic and eosinophilic infiltrates in the peribulbar region.
Acute telogen effluvium
An increased shedding of normal hairs.Alopecia is diffuse.There is a history of physical stressor (high fever, surgery, pregnancy, rapid weight loss, nutritional deficiencies, haemorrhage, or hormonal dysfunction such as thyroid dysfunction) or offending medication use beginning approximately 3 to 5 months prior to onset of shedding.Diffuse hair loss on the scalp with sometimes short regrowing frontal hair, although overall hair density appears normal to minimally decreased.
Hair pull test is usually positive. View imageScalp biopsy does not show miniaturised hair follicles and may appear almost normal except for a variable increase in the proportion of telogen follicles.
Chronic telogen effluvium
This is an idiopathic, abrupt onset of generalised diffuse shedding of telogen hairs from the scalp that may persist up to several years.Occurs more commonly in women.May be distinguished from acute telogen effluvium by its long fluctuating course.Frontoparietal hair loss or widening of the central part is not present, but the disease may be accompanied by bitemporal recession.Women typically present without visible reduction in scalp hair density.The hair loss appears to be self-limiting and does not cause baldness.
Hair pull test is positive only in the active early hair loss phases, but negative in longstanding hair loss. Histopathological evaluation of a scalp biopsy shows a normal-appearing scalp skin.
Anagen effluvium
Anagen hair loss is associated with any damage to the hair follicle that impairs its mitotic activity. Usually occurs after exposure to antineoplastic chemotherapeutic agents that cause immediate interference with hair-shaft formation and shedding of already formed anagen hairs. [19]
Hair pull test will be positive.Predominantly anagen hairs present on microscopic examination of biopsy specimen.
Polycystic ovary syndrome (PCOS)
Patients may present with weight gain, irregular menstruation, infertility and/or hirsutism. Associated symptoms or features are acne and androgenetic alopecia.
Standard diagnostic tests are pelvic ultrasound, although not all women have ovarian cysts, and an androgen profile (total and free testosterone, DHEA-sulphate and sex hormone binding globulin).
Cushing's syndrome
Patients may complain of weight gain presenting as moon face, truncal obesity and buffalo hump. Associated findings are hirsutism, facial flushing, haematomas and striae distensae.
Standard screening tests show elevated 24-hour urine free cortisol levels, late-night salivary cortisol, or lack of suppression on overnight dexamethasone test. High-and low-dose dexamethasone suppression may further identify ACTH-dependent or -independent Cushing's syndrome.
Hyperprolactinaemia
Woman may present with oligomenorrhoea or amenorrhoea. Men may present with sexual dysfunction, headache and/or visual field defects. Galactorrhoea may be an associated finding in both men and women.
Screening test shows elevated serum prolactin levels.
Thyroid dysfunction
Patients with hypothyroidism may present with cold intolerance, fatigue, weight gain, constipation, goiter and/or depression. Associated findings are dry coarse hair and skin.Patients with hyperthyroidism may present with weight loss, increased appetite, heat intolerance, irritability, fatigue and/or cardiac symptoms such as palpitations.Patients with autoimmune disorder may also present with pretibial myxoedema and/or exophthalmus.
Serum test for TSH shows elevated levels in patients with primary hypothyroidism and low or suppressed levels in patients with primary hyperthyroidism.
Iron deficiency
Symptoms may include progressive fatigue, pallor, dyspnoea, and pica. Associated findings are hair loss and brittle nails.
Standard screening tests reveal microcytic anaemia, low serum iron and ferritin levels and high iron binding capacity.

Angiodysplasia of the colon

Diverticular disease
Abdominal cramping, constipation, pain, and diarrhoea are characteristic.
CT scan identifies colonic diverticula, pericolic fat stranding, thickened bowel wall, soft tissue swelling, and abscesses in diverticular disease.Once diverticulitis has subsided, colonoscopy may be performed to determine the extent of disease and to aid in differentiation.
Colorectal cancer
A change in bowel habits, tenesmus, and weight loss are more common in patients with colonic cancer, and are sometimes associated with the presence of an abdominal mass.
Colonoscopy identifies mass lesions, which can then be biopsied.
GI stromal tumours and leiomyomas
These tumours occur mainly in the upper GI tract and present with dysphagia, GI haemorrhage, or metastases (mainly in the liver).
OGD allows identification and biopsy in most cases.
Haemorrhoids
Pruritus ani, haemorrhoid lesions with no haematochezia or melaena on physical examination.
Proctoscopy demonstrates haemorrhoid lesions.
Colonic polyps
There are no differentiating signs and symptoms.
Colonoscopy identifies polyp lesions.
Crohn's disease
Abdominal pain, weight loss, fever, aphthous ulcers, change of bowel habit, and urgency are characteristic.
Colonoscopy identifies patchy inflammation and ulcerations.
Ulcerative colitis
Abdominal pain, weight loss, fever, extra-intestinal manifestations, change of bowel habit, and urgency are characteristic.
Colonoscopy demonstrates continuous erythema, mucosal friability and ulceration, and pseudopolyps in the colon and rectum.
Ischaemic bowel disease
Sudden onset abdominal pain out of proportion to physical signs, a change in bowel habit, nausea, vomiting, and fever.
A high WBC count and low serum bicarbonate level aid in identifying ischaemic bowel disease.Colonoscopy identifies petechial haemorrhages with pale, swollen mucosal areas in early ischaemia. Severe ischaemia is associated with grey, cyanotic, or black mucosa.
Meckel's diverticulum
Abdominal pain, bloating, and symptoms of intestinal obstruction.
A technetium Tc-99m pertechnetate scan is the preferred investigation.
Infectious colitis
Abdominal pain, fever, vomiting, nausea, and diarrhoea are characteristic.
On colonoscopy, infectious colitis may display pseudomembranous tissue.Cultures for Clostridium difficile are recommended in addition to conventional pathogens such as salmonella and campylobacter.

Angle-closure glaucoma

Open-angle glaucoma (primary and secondary)
Clinically indistinguishable from ACG.
Gonioscopy shows an open angle.
Other optic neuropathies (e.g., compressive)
Visual field defects are different from those of glaucoma.
Intraocular pressure is normal. Gonioscopy shows an open angle. Optic nerve atrophy (whitening of tissue) in contrast to loss of tissue and cupping.
Eye trauma
Acute red eye. Usually no nausea or vomiting. Hx of recent trauma.
Intraocular pressure usually normal. Gonioscopy shows an open angle. The anterior chamber depth is usually normal.
Keratitis
Acute red eye. Usually no nausea or vomiting.Conjunctival discharge. Signs of infectious infiltrate in the cornea.
Intraocular pressure usually normal. Gonioscopy shows an open angle. The anterior chamber depth is usually normal.
Conjunctivitis, Acute
Acute red eye. Usually no nausea or vomiting.Conjunctival discharge. Signs of infectious infiltrate in the cornea.
Intraocular pressure usually normal. Gonioscopy shows an open angle. The anterior chamber depth is usually normal.
Corneal ulcer
Acute red eye. Usually no nausea or vomiting.Recent foreign body, contact lens use or known poor eye closure (e.g., facial palsy).
Intraocular pressure usually normal. Gonioscopy shows an open angle. The anterior chamber depth is usually normal.
Episcleritis or scleritis
Acute red eye. Usually no nausea or vomiting.Known systemic disease, such as rheumatoid arthritis.
Intraocular pressure usually normal. Gonioscopy shows an open angle. The anterior chamber depth is usually normal.

Angular cheilitis

Herpes simplex infection
May occur at the corners of the mouth; however, the infection is usually unilateral.These lesions start as macules and, over a few days, become vesicular and then pustular, finally forming a crust and healing. [10] [11]
PCR for HSV is positive.

Animal bites

Soft tissue injury
A complete history should be able to help in differentiating animal bites from another mechanism of injury.
Diagnosis is clinical.

Ankle fractures

Lateral ankle ligament tear (anterior talofibular ligament and calcaneofibular ligament)
Minimal lateral malleolar posterior bony tenderness. There may be a positive anterior drawer sign of the ankle or increased talar tilt depending on extent of the tear. Uncommonly there is significant deformity to the ankle.
Plain x-rays will not identify a fracture.MRI examination or musculoskeletal ultrasound may show oedema with or without a tear to the lateral ankle ligaments (anterior talofibular ligament and calcaneofibular ligament).
Achilles tendon rupture
No malleolar tenderness. There may be a gap in the Achilles tendon and a positive Thompson's test.
Plain x-rays demonstrate no fracture and an MRI or musculoskeletal ultrasound of the Achilles tendon will demonstrate a tear.
Talar fracture
There may be no malleolar tenderness. There may be a deformity to the ankle and hindfoot.
Plain x-rays demonstrate a fracture of the talus.
Syndesmotic disruption
There may be no malleolar tenderness. External rotation test and calf squeeze test may demonstrate pain in the syndesmosis. [20]
Plain x-rays demonstrate no fracture but may show tibiofibular widening.

Ankylosing spondylitis

Osteoarthritis
Presents with mechanical pain typically becoming worse at the end of the day and after activity, with no morning symptoms.May occur after lifting or bending.The history differentiates mechanical back pain from inflammatory back pain.
Radiographs of the back may demonstrate degenerative disc disease or the presence of osteophytes.
Diffuse idiopathic skeletal hyperostosis (DISH)
Typically presents with mechanical symptoms.Age of onset may help differentiate this condition from AS, as onset tends to be in the 50- to 75-year age group.
In DISH there are flowing osteophytes along the anterior margin of the vertebra in the presence of normal vertebral bodies and discs on x-ray. [75]
Psoriatic arthritis
Part of the spondyloarthropathy group.Tends to present in the 35- to 45-year age group. No sex bias.Sacroiliitis may be unilateral.History of psoriasis.Dactylitis more common.
Hand and foot x-rays may reveal erosive disease.
Reactive arthritis
Patients usually recall a specific infection: for example, a non-gonococcal urethritis or gastroenteritis.Dactylitis and skin manifestations occur more frequently than in AS.May present with keratoderma blennorrhagica, conjunctivitis, or urethral discharge.
Pelvic x-rays may demonstrate unilateral sacroiliitis.
Inflammatory bowel-related arthritis
Hx Crohn's disease or ulcerative colitis.No sex bias.Peripheral joint involvement common.May have evidence of erythema nodosum or pyoderma gangrenosum.
Only 30% HLA-B27-positive.May have unilateral sacroiliitis.
Infection (e.g., discitis)
Patients are usually systemically ill with fever, anorexia, and rigors accompanying back pain.
Focal spinal abnormalities on x-ray or MRI.Elevated inflammatory markers.
Vertebral fracture
May co-exist with AS.Presents as episodic spinal pain.
Focal spinal abnormalities on x-ray or MRI.
Bony metastases
Systemic clues such as weight loss, melaena, alternating bowel habits, prostate symptoms, breast mass.
Radiographs more likely to show vertebral collapse or metastatic deposits.
Onchronotic arthropathy
Rare syndromes, which present in the 3rd and 4th decades with lower back and hip stiffness that can mimic AS.
Presence of homogentisic acid in the blood and urine.

Anorectal abscess

Anal fissure
Pain occurs primarily during bowel movements and may improve in the next few hours. Anal fissures are frequently associated with rectal bleeding.Physical examination can distinguish between the 2 conditions although anaesthesia will occasionally be needed for an adequate examination. On physical examination, fissures are located in the anterior or posterior midline, are without induration, and are tender to palpation. Secondary finding of an anal fissure may be present (sentinel pile).
Diagnosis is usually clinical. However, MRI or CT pelvis may be used in difficult-to-examine cases to exclude anal fissure (both investigations are very sensitive and specific for anorectal abscesses).
Thrombosed haemorrhoid
Usually presents with the sudden onset of perianal pain and swelling.On physical examination, thrombosed haemorrhoids are swollen, with minimal induration or signs of inflammation, and are frequently bluish in colour.
Diagnosis is clinical.
Pilonidal abscess
Very difficult to distinguish clinically, but physical examination may do so. While anorectal abscesses are usually immediately adjacent to the anus, pilonidal abscesses are characteristically located in the inter-gluteal region and frequently have a visible sinus tract in the midline.
MRI or CT pelvis may be used in difficult-to-examine cases to exclude pilonidal abscess (both investigations are very sensitive and specific for anorectal abscesses).
Infected epidermoid inclusion cyst
Difficult to distinguish clinically, but physical examination can do so in some cases. While anorectal abscesses are usually immediately adjacent to the anus, infected epidermoid inclusion cysts are more commonly >3 cm from the anal verge.
MRI or CT pelvis may be used in difficult-to-examine cases to exclude infected epidermoid inclusion cyst (both investigations are very sensitive and specific for anorectal abscesses).
Perianal hidradenitis suppurativa
The presenting signs and symptoms are the same as those for anorectal abscesses, but physical examination can often distinguish between the conditions. Perianal hidradenitis suppurativa is usually associated with hidradenitis in other areas, most commonly the axilla and inguinal areas. While anorectal abscesses are usually single, abscesses associated with hidradenitis are more commonly multiple and usually associated with purulent drainage from multiple sinus tracts.
Diagnosis is usually clinical.
STDs
History of anal-receptive sex with or without immunosuppression (e.g., HIV), rectal discharge, severe anal pain, malaise may be present.Physical examination may reveal systemic fever, lymphadenopathy, anal discharge. In addition, rectal examination, usually under anaesthesia, will reveal rectal mucosal changes consistent with proctitis.
Rectal swab for microscopy, Gram stain, and culture usually reveals the causative organism (e.g., Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes simplex, Treponema pallidum).In addition, stool microscopy and culture, serological testing, and tissue biopsy may help confirm diagnosis.

Anorexia nervosa

Bulimia nervosa
Complain of bloating, abdominal pain, sore throat, and a feeling of fullness.
No differentiating test exists.
Depression
Often show poor concentration and poor self-esteem, not solely linked to weight gain or loss.
No differentiating test exists.
Hyperthyroidism
Weight loss with additional symptoms of heat intolerance, hyperactivity, polyuria, sweating, nausea with vomiting, diarrhoea, and tremors.
TFTs show TSH as normal, high T4 and T3.
Type 1 diabetes mellitus
History of blurred vision, polyuria, polydipsia, and polyphagia are common with weight loss, but without purging.
A fasting plasma glucose level of ≥126 mg/dL (≥ 6.7 mmol/L) and a plasma glucose of 200 mg/dL (11.1 mmol/L) or increased 2 hours after an oral load of 75 mg glucose,or elevated levels of haemoglobin A1c is diagnostic.
Crohn's disease
May have abdominal pain, bloody stools, and possibly arthritic pain in addition to weight loss. Patients do not avoid food for fear of gaining weight.
Colonoscopy with biopsy will show inflammatory tissue changes.
Ulcerative colitis
May have abdominal pain, bloody stools, and possibly arthritic pain in addition to weight loss.
Colonoscopy with biopsy will show inflammatory tissue changes.
Obsessive-compulsive disorder (OCD)
OCD often presents similarly, with ritualised eating habits. However, OCD is characterised by obsessions unrelated to food, such as a fear of death. Medication may be effective, unlike in anorexia. [40]
No differentiating test exists.
Cancer (any type)
Weight loss unintentional without fear of weight gain or body image disruption.
FBC may show anaemia. If warranted, biopsy, cytology, and imaging should be carried out.
HIV infection
May have a history of fever, headache, aching muscles, sore throat, and often swollen lymph nodes, mouth and oesophageal ulcers, and rash in addition to weight loss.
Distinguished by an HIV test.

Anterior cruciate ligament injury

Medial collateral ligament (MCL) sprain
The pop sound at injury is less common and true dynamic instability is rare, unless it is a complete tear or with associated injuries. May be able to continue activity if minor sprain. No significant haemarthrosis in isolated MCL sprain, although reactive effusion not uncommon. Tender over MCL course/insertion. MCL stress testing reveals laxity and/or pain. Additionally, Lachman's and pivot shift tests are negative. Spontaneous healing and full return of function is the rule. [58]
MRI reveals fluid around or injury to MCL; ACL appears intact. Subsequent x-rays may reveal calcification along previously injured MCL (Pellegrini-Stieda disease).
Posterior collateral ligament (PCL) sprain
Often able to continue activity but knee does not feel right subjectively to the patient. Instability may be more subtle, with knee effusion typically smaller and less noticeable by the patient. Lachman's,View image pivot shift, anterior drawer tests are negative, but the posterior drawer test is positive.View image External rotation recurvatum test will show posterolateral corner instability.View image Unlike with ACL tears, non-operative approach often allows return to full activity. [59]
MRI reveals disrupted PCL, and an intact ACL.
Lateral collateral ligament (LCL) sprain
Local swelling is common, but significant effusion is rare. There is tenderness over the lateral collateral ligament and/or bony insertion. A complete tear often results in a palpable gap. Spontaneous healing and full return of function is the rule. [60]
MRI reveals fluid around or disruption to LCL, with intact ACL.
Meniscal tear
Meniscal injury may also occur with ACL tear or other significant injury. Main symptom is pain at affected joint line and stiffness. Effusion typically develops over 1 to 2 days, but rapid haemarthrosis may occur if large tear in vascular portion of meniscus. [61] [62]Physical examination manoeuvres have poor accuracy, but joint line tenderness is common, as is pain with rotational manoeuvres (e.g., positive McMurray's testView imageView imageView imageView image).
MRI has excellent sensitivity for meniscal tears, but intra-substance degenerative changes may be misread as acute tears. [63]
Posterior capsular sprain
Small effusion and stiffness common, along with painful extension. ACL and other ligaments are stable. [64]
Imaging rarely necessary. MRI may show effusion, bone bruising, abnormal signal at posterior capsule, but no frank ligament disruption.
Patellar subluxation or dislocation
Patient feels severe pain around patella; may see kneecap off to the side. Haemarthrosis occurs, with difficulty in weight bearing, and a sensation of the kneecap being unstable. Examination usually reveals haemarthrosis, tenderness at patella and medial retinaculum, and apprehension when examiner attempts to displace patella laterally. ACL testing should be normal. [65]
X-rays may reveal dislocation if not yet reduced, or patellar fracture. Lateral subluxation and abnormal patellofemoral relationship often noted. MRI often reveals bone bruising, and may show chondral injury, osteochondral fracture, or loose body. [66]

Anthrax

Bacterial furunculosis
Lesions of staphylococcal or streptococcal furunculosis are typically painful, whereas cutaneous anthrax lesions are painless. Bacterial furunculosis may also be suggested by the recurrence of fevers, lymphangitis, and purulent drainage. [2]
Wound Gram stain and cultures in bacterial furunculosis should reveal typical pathogens, such as Staphylococcus or Streptococcus.
Ecthyma gangrenosum
Occurs in patients with neutropenia.
Blood cultures or tissue cultures will reveal typical pathogens associated with ecthyma gangrenosum, such as Pseudomonas aeruginosa, Staphylococcus, and Candida.
Orf (ecthyma contagiosum)
In cases of orf, a scab forms but the distinctive eschar of cutaneous anthrax is absent. In addition, the notable oedema associated with anthrax does not occur. Cases of orf are distinguished by clinical and historical clues relating to contact with infected sheep or goat flesh.
Histological examination of orf reveals epidermal hyperplasia, necrosis, pseudoneoplastic vesicular proliferation, and dermal infiltration with eosinophilic dominance. [53]
Brown recluse spider bite
Brown recluse spider bites are associated with pain, while lesions of cutaneous anthrax are classically painless. In addition, the notable oedema associated with anthrax does not occur. Cases of brown recluse spider bites occur in endemic regions. The brown recluse spider, Loxosceles, can be found in south-eastern Nebraska, Kansas, Oklahoma, Texas, Louisiana, Arkansas, Missouri, Kentucky, Tennessee, Mississippi, Alabama, northern Georgia, and southern portions of Ohio, Indiana, Illinois, and Iowa. [54]
Blood or wound cultures would not find B anthracis.
Influenza infection
Symptoms of malaise, fatigue, low-grade fever, and dyspnoea associated with early inhalational anthrax may resemble influenza. However, coryza, pharyngitis, and nasal congestion do not occur in cases of anthrax. [55]
Anthrax cases may be distinguished from influenza by the presence of a widened mediastinum on CXR. Rapid antigen assays and oropharyngeal viral cultures may be useful if positive for influenza.
Mycoplasma pneumonia
Pneumonia and inhalational anthrax may both present with coughing and fever; however, anthrax is differentiated by additional symptoms of loss of consciousness, dizziness, confusion, nausea, vomiting, and SOB.
Blood cultures would not find B anthracis.Rise in titre of Mycoplasma-specific Ig on convalescent serum.Positive molecular diagnosis from nasopharyngeal aspirate, sputum, or throat swabs.
Viral pneumonia
Viral pneumonia and inhalational anthrax may both present with coughing and fever; however, anthrax is differentiated by additional symptoms of loss of consciousness, dizziness, confusion, nausea, vomiting, and SOB. Additionally, viral pneumonia may present with sore throat and runny nose, not found with anthrax.
Blood cultures would not find B anthracis.
Bronchitis
Bronchitis and inhalational anthrax may both present with coughing; however, anthrax is differentiated by additional symptoms of loss of consciousness, dizziness, confusion, nausea, vomiting, and SOB.
There are no differentiating tests.
Ruptured aortic aneurysm
Cardiovascular collapse secondary to a ruptured aortic aneurysm may occur alongside a history of cardiovascular disease, high cholesterol, and HTN, not found with inhalational anthrax.
An x-ray shows mediastinal widening much like with a ruptured aortic aneurysm; however, mediastinal changes in anthrax occur early in the infection along with pulmonary oedema.
Superior vena cava syndrome
Cardiovascular collapse secondary to superior vena cava syndrome must be differentiated from inhalational anthrax.
An x-ray shows mediastinal widening much like with superior vena cava syndrome; however, mediastinal changes in anthrax occur early in the infection along with pulmonary oedema.
Subarachnoid haemorrhage
May be confused with haemorrhagic meningitis; however, anthrax usually has a history of occupational exposure.
A subarachnoid haemorrhage may be differentiated from haemorrhagic meningitis on CT scan, Gram stain, and culture of CSF.
Viral gastroenteritis
Nausea and vomiting may accompany both diagnoses; however, GI anthrax often has rebound abdominal tenderness, ascites, oropharyngeal mucosal ulceration, or pseudomembrane formation. [46]
Cultures of blood, peritoneal fluid, or oropharyngeal secretions may yield B anthracis. Standard blood cultures effectively grow B anthracis in 6 to 24 hours. Further confirmatory testing (immunohistochemical staining, gamma phage, PCR assays) must be performed by a reference site of the Laboratory Response Network site, if in the US, or according to local protocols in other countries. [1]
Cowpox
Coxpox lesions, characterised by blister formation and scab development resembling eschar, can occur when humans are in direct contact with cowpox ulcers on the cow’s udder. Cases are distinguished by historical clues and contact with the affected animal.
There are no differentiating tests.

Antiphospholipid syndrome

Sneddon's syndrome
First described in 1965, this is the presentation of both livedo reticularis with stroke and hypertension in the absence of a recognised collagen vascular disease or infection.
Antiphospholipid antibodies may be present but are not a diagnostic criterion for Sneddon's syndrome.
Inherited thrombophilia
Presents with venous thrombosis (in particular, apparently spontaneous events) at an early age; FHx of VTE .
Reduced levels of protein C, free protein S level, and antithrombin III level; prothrombin gene mutation (G-20210-A).

Aortic coarctation

Aortic stenosis (AS)
Presenting features vary depending on the severity of stenosis. With mild AS, the patient may be asymptomatic with a harsh systolic ejection quality murmur at the upper right sternal border with radiation to the carotids on physical examination. In moderate or severe AS, the patient may have significant SOB, especially on exertion.
Differentiated from coarctation of the aorta by echocardiogram.Two-dimensional echocardiogram of the aortic valve shows an abnormally narrowed or dysplastic aortic valve.Colour Doppler and pulse Doppler across the aortic valve show turbulent blood flow across the valve and are used to measure the gradient.Patients with aortic coarctation with associated bicuspid aortic valve may also have AS.
Interrupted aortic arch
Presents as shock in neonates. Unable to clinically differentiate between interruption of the aortic arch and critical coarctation of the aorta.
Echocardiogram will differentiate the severe narrowing seen in critical coarctation from a frank interruption.
Left ventricular outflow tract obstruction
Depending on the level and severity of the obstruction, patients may be asymptomatic or may present with SOB, especially on exertion.
An echocardiogram will differentiate the level of the obstructed or narrowed area in the aorta. Using colour and pulse Doppler, any narrowing in the left ventricular outflow tract can be localised to the valvar, sub-valvar, or supra-valvar area, or across the aortic arch.
Essential hypertension
Similar clinical presentation.Lower extremity pulses usually normal unless peripheral vascular disease present.
Four-extremity BP shows no gradient.Echocardiogram shows normal flow across the aortic arch and normal Doppler of the abdominal aorta.
Renal artery stenosis
Similar clinical presentation.
Renal artery Doppler shows renal artery stenosis.Normal echocardiogram.
Phaeochromocytoma
Hypertension with associated symptoms such as palpitations and flushing.
A 24-hour urine collection is positive for elevated urine creatinine, metanephrines, and catecholamines.

Aortic dissection

Acute coronary syndrome
Chest pain is typically pressing.There may be a history of prior exertional chest pain.
ECG and troponin T may indicate myocardial infarction or ischaemia.ST segment depression may occur in acute dissection, but ST elevation rare.
Pericarditis
Chest pain typically pleuritic.
ECG typically shows diffuse ST elevation.
Aortic aneurysm
Stable (non-dissecting and non-leaking) aneurysms are asymptomatic. Diagnosis is usually incidental to workup for another entity.
CT scan of the chest does not show dissection.
Musculoskeletal pain
Pain may be reproducible on palpation of the affected area.
CT scan of the chest does not show dissection.
Pulmonary embolus
Dyspnoea, hypoxia and pleuritic chest pain.There may be evidence of deep vein thrombosis, for example, calf swelling or tenderness.
CT scan of the chest shows pulmonary embolus.
Mediastinal tumour
Possible cough or haemoptysis.
CT scan of the chest shows evidence of tumour.

Aortic regurgitation

Mitral regurgitation (MR)
Distinguishing signs are right ventricular heave, soft S1, split S2, and aloud P2. The classical murmur of MR is pansystolic at the apex radiating to the axilla.
CXR: pulmonary oedema, enlarged left atrium and left ventricle, and mitral valve calcification.ECG: can present with atrial fibrillation.Echocardiography: for MR it is used to assess left ventricular function.
Mitral stenosis
Distinguishing features are a malar flush, low volume pulse, a tapping and undisplaced apex beat, and loud S1 with an opening snap.The murmur is a rumbling mid-diastolic one, which can be distinguished from the Austin Flint murmur sometimes heard in severe AR by the absence of the opening snap and loud S1.
CXR: pulmonary oedema, enlarged left atrium, and mitral valve calcification.ECG: can present with atrial fibrillation. RVH may also be present.Echocardiography: diagnostic for mitral stenosis.
Aortic stenosis
Presentation includes dyspnoea, dizziness, fainting, and congestive cardiac failure.Characteristic signs are a slow rising pulse, heaving but undisplaced apex bear, left ventricular heave, and an ejection systolic murmur that radiates towards the carotids and can have an ejection click. This can be distinguished from the ejection systolic murmur that is sometimes heard with moderate or severe AR by absence of an ejection click and no radiation towards the carotids.
CXR: LVH, calcified aortic valve.ECG: P-mitrale, LVH with strain pattern, left bundle branch block, or complete AV block.Echocardiography: diagnostic for aortic stenosis.
Pulmonary regurgitation
Diamond-shaped diastolic murmur best heard in the second and third left intercostal spaces. The murmur increases with inspiration, and P2 is loud in the presence of pulmonary artery hypertension.
CXR: may show dilation of main pulmonary artery with right ventricular dilation.ECG: right ventricular hypertrophy is usually present.Echocardiography: diagnostic for pulmonary regurgitation.

Aortic stenosis

Aortic sclerosis
The murmur of aortic sclerosis is usually less than grade 2 and the aortic closure sound is usually physiologically split. Signs and symptoms of heart failure or chest pain should prompt an echocardiogram but cannot by themselves reliably distinguish the 2 conditions.
Transthoracic Doppler echo will demonstrate no significant pressure gradient (<5 mmHg) across the aortic valve with aortic sclerosis.
Ischaemic heart disease
AS and CAD frequently co-exist and it is difficult to determine their relative contributions to cardiac complaints when both are present in the same patient.In practice, for patients with severe AS and concomitant CAD, both are treated at the time of surgery.
In ischaemic heart disease, common ECG findings include Q waves in contiguous leads, and the echocardiogram often shows segments of the myocardium with abnormal systolic thickening or wall motion abnormalities.In AS, Q waves are absent in the ECG; regional wall motion abnormalities are absent on the echocardiogram; and coronary arteries are normal upon cardiac catheterisation.
Hypertrophic cardiomyopathy (HCM)
HCM is a heterogeneous disease that can produce subvalvular stenosis and a murmur that is identical to AS.Hand gripping and squatting manoeuvres are helpful in distinguishing HCM from AS. These manoeuvres do not greatly affect the intensity of the murmur of AS; however, hand gripping, which increases afterload, will soften the HCM murmur. Standing up after squatting will decrease cardiac return and ventricular preload, which increases the murmur of HCM.
Typical echocardiography findings include asymmetric hypertrophy with the septal wall most prominently affected. Dynamic obstruction is observed at the subvalvular level, and calcification of the valve is often absent, especially in younger patients. [19]

Aphthous ulcers

Behcet's syndrome
Patients may present with aphthous-like ulcers occurring on genital or other mucosae; erythema nodosum, or other skin lesions; uveitis; joint involvement; or CNS manifestations. [1] [21]Seen most commonly in the Middle East, in the Far East, and around the Mediterranean.
Diagnosis is based on hx and clinical features.Pathergy test is positive in up to 60% of patients, with highest frequency in those of Middle Eastern origin.May be HLA-B51 genotype, although this association varies with ethnicity.
Malignant ulcer
Persistent ulcers (i.e., the ulcer does not heal) are typical of malignant disease (e.g., oral carcinoma).Lesion may be indurated and painless; cervical lymphadenopathy may be present.
Incisional biopsy will show malignant disease (most commonly squamous cell carcinoma or lymphoma).
Folate deficiency
Hx of a diet poor in sources of folate or heavy alcohol use.Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result from the anaemia.
Anaemia is macrocytic (MCV >100 fL); serum folate low (<6 nanomol/L [<2.5 nanogram/mL]); RBC folate level <317 nanomol/L (<140 nanogram/mL).
Iron deficiency anaemia
May present with glossitis, angular stomatitis, and spooning of the nails.Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result from the anaemia.
Ferritin is typically low (<112 picomol/L [<50 nanogram/mL]) in iron deficiency; a ferritin level of <34 picomol/L (<15 nanogram/mL) strongly suggests iron deficiency.
Vitamin B12 deficiency
May present with evidence of peripheral neuropathy or posterior column degeneration (e.g., ataxia).Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result from the anaemia.
Anaemia is typically macrocytic (MCV >100 fL); serum B12 is low (<148 picomol/L [<200 picogram/mL]).
HIV infection
Intra-oral infections (candidiasis, hairy leukoplakia) or neoplasms (Kaposi's sarcoma, lymphoma); other clinical evidence of, or risk factors for, HIV infection.In HIV infection, aphthous-like ulceration may be seen independent of the necrotising ulceration of HIV infection. [28]
Diagnosis is based on hx and clinical features.HIV serology will be positive.
Crohn's disease
Crohn's disease can affect any part of the gastrointestinal tract and symptoms may be extremely variable.Features may include: bloody diarrhoea; weight loss; labial or facial swelling; and, occasionally, joint manifestations.
Colonoscopy will show mucosal inflammation and discrete deep, superficial ulcers located transversely and longitudinally, creating a cobblestone appearance.Full-thickness bowel biopsies demonstrate transmural involvement with non-caseating granulomas.
Ulcerative colitis
UC typically presents with features of colitis including left-sided abdominal pain and bloody diarrhoea.
Colonoscopy will show rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas (rarely seen), and normal terminal ileum (or mild 'backwash' ileitis in pancolitis).Bowel biopsies will show mucin depletion, basal plasmacytosis, and diffuse mucosal atrophy.
Coeliac sprue
Patients typically present with unexplained gastrointestinal symptoms, chronic diarrhoea, unexplained iron deficiency anaemia, or a skin rash consistent with dermatitis herpetiformis.
Diagnosis is suggested by positive immunoglobulin A tissue transglutaminase serology.Duodenal endoscopy will show atrophy and scalloping of mucosal folds, nodularity, and mosaic pattern of mucosa; histology will show presence of intra-epithelial lymphocytes, villous atrophy, and crypt hyperplasia.
MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome
A variant of Behcet's syndrome.A generalised chondritis may be present. [22]
Diagnosis is based on hx and clinical features.
Cyclic neutropenia
Patients may present with recurrent fevers and recurrent infections. [23]
Diagnosis is based on hx and clinical features.FBC may show leucopenia.
PFAPA (periodic fever with aphthae pharyngitis and adenitis) syndrome
Comprises periodic fever, aphthae, pharyngitis, and cervical adenitis.Although rare, it tends to occur in young children. [24]
Diagnosis is based on hx and clinical features.FBC may show leucopenia.
TRAPS (tumour necrosis factor receptor-associated periodic syndrome)
Comprises periodic fever and aphthae. [25]
Diagnosis is based on hx and clinical features.FBC may show raised ESR.
Sweet syndrome
Patients have ulceration similar to recurrent aphthous stomatitis (RAS) but with sudden onset of fever, and well-demarcated plum-coloured skin lesions. [29]There is an associated malignancy (e.g., acute myeloid leukemia) in 50% of patients.
Diagnosis is based on hx and clinical features.FBC may show leucocytosis.
Pemphigus vulgaris
The early phages of pemphigus may be characterised by recurring oral ulcers. [1] [30]
Incisional biopsy and histopathology may show characteristic findings of pemphigus: epithelial acantholysis with supra-basal blistering.Direct immunofluorescence will show staining for IgG, C3, or both in a broad linear band on the surface of keratinocytes in the suprabasal epithelium.
Infectious mononucleosis (EBV)
Small superficial ulcers of the oral mucosa may be a feature of EBV infection.
Diagnosis is based on history and clinical features.FBC will show lymphocytosis and atypical lymphocytosis.Serology will be positive for EBV-specific antibodies: VCA-IgM, VCA-IgG, EA, EBNA.

Aplastic anaemia

radiation injury
History of radiation exposure to marrow-bearing areas.
Clinical diagnosis.
chemotherapy
History of chemotherapy.
Clinical diagnosis.
HIV infection
History of HIV risk factors or opportunistic infections.
HIV testing positive.
vitamin B12 deficiency
Dietary history of deficiency.Intestinal disease or resection.Neurological abnormalities.
Serum B12 levels below lower limit of normal; macrocytic anaemia; megaloblastic changes in bone marrow cells.
folate deficiency
Dietary history of deficiency.Intestinal disease or resection.
Folate levels below lower limit of normal; macrocytic anaemia; megaloblastic changes in bone marrow cells.
hypothyroidism
May be asymptomatic, or may present with low energy, weight gain despite poor appetite, and changes in hair and skin texture.
TSH elevated, and free T4 low.
systemic lupus erythematosus
Classically, butterfly rash, joint pains.
SLE and some other connective tissue disorders can cause pancytopenia through an autoimmune mechanism.Positive ANA and anti-double-stranded DNA can help diagnose SLE.Marrow usually cellular or fibrotic, although rarely may also be hypocellular.
TB and atypical mycobacterial infections
May include cough, lymphadenopathy, weight loss.
Acid-fast bacilli stain or mycobacterial culture from an involved site can diagnose these infections.Bone marrow is not hypocellular (and may show granulomata in TB).
ehrlichiosis
Severe headache, myalgias, fever, chills.
Bone marrow not hypocellular.Ehrlichiosis IgG titre elevated.
Legionella infection
Fever, myalgia, malaise, cough initially dry then becomes productive.
Urine legionella antigen positive.Bone marrow not hypocellular.
overwhelming sepsis
Fever or hypothermia. Hypotension. Poor peripheral perfusion. Multiorgan failure.
Blood cultures positive.Bone marrow not hypocellular.
hypocellular myelodysplastic syndrome (MDS)
May have no differentiating clinical features.Might have history of exposure to leukaemogenic agents (e.g., alkylating agents, topoisomerase II inhibitors, and radiation).Can be complication of AA.
The following features of the bone marrow examination may suggest MDS: [13]1) prominent dysplasia on marrow or peripheral blood examination (particularly in the myeloid and megakaryocyte lineages; AA can often show some erythroid dysplasia)2) circulating blasts or an increased number of marrow blasts (or CD34+ cells on immunohistochemical staining)3) presence of an increased proportion of ringed sideroblasts in the marrow4) marrow fibrosis5) cytogenetic abnormalities (especially abnormalities of chromosome 5 or 7, trisomy 8, 20q-, trisomy 21 or complex karyotypes), but AA can also be associated with cytogenetic abnormalities.
hypocellular acute myelogenous leukaemia (AML)
Constitutional and often related to cytopenias: weakness, low energy, pallor, easy bruising, easy bleeding.
Peripheral blood smear may show blasts.Bone marrow examination reveals abnormal cell population.
multiple myeloma
Often asymptomatic. May have symptoms related to cytopenias: weakness, low energy, pallor, easy bruising, easy bleeding.
Monoclonal urine Ig spike.Careful bone marrow examination reveals abnormal cell population.
non-Hodgkin's lymphomas
May have lymphadenopathy, night sweats, weight loss, or anorexia.May have symptoms related to cytopenias: weakness, low energy, pallor, easy bruising, easy bleeding.
Bone marrow examination reveals abnormal cell population.
Hodgkin's lymphoma
May have lymphadenopathy.May have night sweats, weight loss, anorexia.May have symptoms related to cytopenias: weakness, low energy, pallor, easy bruising, easy bleeding.
Bone marrow examination reveals abnormal cell population, usually clonal.Characteristic Reed-Sternberg cells may be seen on bone marrow biopsy.
carcinoma metastatic to marrow
Primary tumour is usually apparent by the time metastasis causes pancytopenia.
Metastatic cells in bone marrow.
hypocellular acute lymphoblastic leukaemia (ALL)
May present with features of pancytopenia; hypocellular ALL occurs in 1% to 2% of childhood ALL.
CBC shows pancytopenia with neutropenia more pronounced than thrombocytopenia.Peripheral blood smear may show blasts.Bone marrow examination reveals abnormal cell population and may show increased reticulin.
Hairy cell leukaemia
Symptoms of pancytopenia, often with splenomegaly.
CBC shows pancytopenia but with accompanying monocytopenia.
anorexia nervosa or prolonged starvation
Underweight.
Bone marrow may show hypocellularity with gelatinous transformation, loss of fat cells, and presence of increased ground substance on haematoxylin and eosin staining.

Asbestosis

Idiopathic pulmonary fibrosis
Absence of history of significant exposure to asbestos after obtaining complete work and environmental history.Signs and symptoms same as for asbestosis.
Lung biopsy does not show asbestos bodies or quantification of mineral content of increased asbestos mineral fibres.
Connective tissue disease
Patients with a history of rheumatoid arthritis, scleroderma and SLE may develop pulmonary fibrosis.Absence of history of significant exposure to asbestos after obtaining complete work and environmental history.Same symptoms of dyspnoea. Will have specific signs and symptoms of arthritis, skin rash, liver or renal disease related to the particular connective tissue disease.
Lung biopsy does not show asbestos bodies or quantification of mineral content of increased asbestos mineral fibres.Immunological markers such as RF and ANA are non-specific and may be present in patient with asbestosis without connective tissue disease. [18]
Hypersensitivity pneumonitis (HP)
Absence of history of significant exposure to asbestos after obtaining complete work and environmental history.Respiratory symptoms are typically associated with acute exposure to causal antigen such bacteria or mould in silage or hay. With subacute or chronic HP this temporal association may not be appreciated.
Presence of IgG antibodies in the blood to the causal antigen, a ground glass appearance on HRCT and granulomas on lung biopsy.
Hard metal lung disease
History of exposure to work with release of tungsten carbide into the air.Similar clinical presentation.
Lung biopsy has pathognomonic giant cells that are unique to the disease.
Silicosis
History of exposure to silica. In certain workplaces, such as foundries and mines, workers may be exposed to both silica and asbestos. [19]Similar clinical presentation.
CXR of silicosis is very different, with small rounded opacities initially beginning in the upper lobes. With progression, these smaller nodules conglomerate into large opacities (progressive massive fibrosis). Unlike asbestos exposure, there are no pleural changes seen.Lung biopsy shows pathognomonic silicotic nodules. Some patients with exposure to asbestos and silica may have radiographical and/or pathological changes of mixed dust.
Sarcoidosis
Absence of history of significant exposure to asbestos after obtaining complete work and environmental history.Same respiratory symptoms, but also involves other organs.
Imaging shows hilar lymphadenopathy and predominately upper lobe scarring.May be associated with hypercalcaemia.Granulomas on biopsy.
Medication or radiation-related pulmonary fibrosis
History of taking medicines such as amiodarone, nitrofurantoin, methotrexate, bleomycin and cyclophosphamide, or receiving radiotherapy.Same respiratory symptoms.
No differentiating investigations.

Ascariasis

Asthma in adults
Patients present with repeated episodes of coughing, wheezing, chest tightness, and dyspnoea. There may be an identifiable trigger (e.g., tobacco smoke, certain animals, or exercise).
Diagnosis is confirmed using pulmonary function tests (PFTs). CXR may be normal or may show evidence of underlying infection.
Viral gastroenteritis
Self-limiting watery diarrhoea, vomiting, or both, with or without fever, malaise, and anorexia, are common presenting symptoms. Diarrhoea and vomiting are less common in ascariasis.
It is not usually necessary to perform stool examinations on patients with viral gastroenteritis. However, a stool sample should be obtained if there is an outbreak, to identify the pathogen as quickly as possible. Stool culture is the most definitive diagnostic test in identification of viral pathogens, but this is not practical in most cases. Latex agglutination tests, polymerase chain reaction (PCR), microscopy, enzyme immunoassay (EIA), or serology allows rapid detection, but these are usually not necessary.
Amoebiasis
Usual presentation is with diarrhoea that lasts several days, abdominal pain, and weight loss. If there is hepatic infection, then jaundice, RUQ pain, and hepatomegaly may also be present.
Patients with amoebiasis may have stool ova and parasites positive for characteristic trophozoites or cysts, or a positive serological test for Entamoeba histolytica.
Salmonella infection
Presents with nausea, vomiting, and diarrhoea. The patient may also complain of headaches, abdominal pain, fever, or myalgia. There may be history of the patient eating contaminated food (e.g., undercooked eggs or meat).
Stool or blood culture may grow Salmonella.
Strongyloides infection
Presents with abdominal pain, diarrhoea or constipation, weight loss, skin changes such as dermatitis or pruritus, and pulmonary complaints such as wheezing or coughing.There may be a history of travel to an endemic country (e.g., many tropical and sub-tropical regions worldwide, Appalachian region of the US, and certain Mediterranean regions, especially Catalonia, Spain).
Patients with strongyloidiasis may have larvae in stool or sputum, or a positive serology test for S. stercoralis.
Pancreatitis
Abdominal pain is usually severe, epigastric, and radiating towards the back. It is usually accompanied by fever, nausea, and vomiting. There may also be voluntary abdominal guarding and mild abdominal rigidity with rebound tenderness.
Raised serum amylase and lipase are key to diagnosis.
Cholecystitis
Presents with RUQ pain, nausea, and a positive Murphy's sign. There may be a history of previous similar episodes or of known gallstones.
Ultrasound of RUQ may show pericholecystic fluid, distended gallbladder, thickened gallbladder wall, or gallstones.
Acute appendicitis
Typically presents with constant mid-abdominal pain that moves to the RLQ. Pain worse on movement. Anorexia, nausea, and low-grade fever are common.
Diagnosis is usually clinical. However, an FBC could show mild leukocytosis. Further investigations, such as abdominal ultrasound or CT, are indicated in atypical presentations.
Ancylostomiasis
Patients with heavy hookworm infections (Ancylostoma duodenale or Necator americanus) may develop a cough characteristic of Loeffler's syndrome.A patient may occasionally become host to A caninum or A braziliense, the dog and cat hookworms, and may also develop a cough characteristic of Loeffler's syndrome. Examination also reveals itchy red papules consistent with a creeping eruption associated with this infection. As larvae migrate through the skin, pruritic serpiginous tracks are formed.
Stool studies may demonstrate hookworm eggs.Eggs are not noted in stool studies in patients who are host to the dog or cat hookworm.Patients with hookworm infection may demonstrate hypochromic microcytic anaemia on FBC.
Trichuriasis
Also called whipworm infection. May present with abdominal pain, bloody diarrhoea, and tenesmus. Chronic infection can lead to Trichuris trichiura colitis, which is similar to inflammatory bowel disease.
Stool studies reveal characteristic eggs. Anoscopy may also demonstrate worms on visualisation of the rectum.

Ascending cholangitis

Acute cholecystitis
Positive Murphy's sign (inhibition of inspiration by pain on RUQ palpation).Murphy's sign is most commonly associated with cholecystitis, which can occur alongside cholangitis but this rarely happens in clinical practice. People with cholangitis typically have diffuse RUQ pain and not classic Murphy's sign
Transabdominal ultrasound: pericholecystic fluid and gallbladder wall thickening.Abnormal hepatic imido-diacetic acid (HIDA) scan.
Peptic ulcer disease
Symptoms often improve with food and antacids. Pain can last a few weeks and remit for a period of time.
LFTs typically normal.
Acute pancreatitis
History of alcohol consumption, or medication-induced or chronic pancreatitis.Pain is often more severe than that experienced with cholangitis.It is important to note that cholangitis can occur in the setting of acute or chronic pancreatitis but is less common.
Amylase: greater elevation when compared with cholangitis.Lipase: raised levels are more specific to the pancreas than amylase levels.CT scan: often shows stranding around the pancreas.
Hepatic abscess
Hepatomegaly, acute abdomen.It is important to note that acute cholangitis can cause hepatic abscesses, but in the case of hepatic abscess alone, bile ducts are much less likely to be dilated.
Ultrasound, CT, or MRI will typically identify the abscess.
Acute pyelonephritis
Flank pain, costovertebral angle tenderness.
Urinalysis: pyuria, positive nitrites.CT scan may show perinephric stranding.
Acute appendicitis
McBurney's point tenderness, Rovsing's sign, obturator sign (pain with passive flexion and internal rotation of the right hip), acute abdomen on examination with rebound, guarding or rigidity.
CT scan of the abdomen: fat stranding around the appendix, thickening of the appendix, periappendiceal fluid.
Right lower lobe pneumonia
Positive history of cough, shortness of breath. Physical examination will have crackles on lung auscultation.
CT scan of the abdomen usually images the lower lung lobes and will show a consolidation.
HELLP syndrome of pre-eclampsia
Haemolysis, raised liver enzymes, and low platelet count (HELLP) syndrome indicates the presence of haemolytic anaemia, raised liver enzymes, and low platelet count. It typically occurs in the latter stages of pregnancy and is considered a form of pre-eclampsia. A small percentage of cases occur after delivery.Raised BP.
Fibrin degradation products: raised.Lactate dehydrogenase: raised (marker of haemolysis).Urinalysis: proteinuria.

Asperger's syndrome

Autistic disorder
Delayed single-word or phrase speech is required for diagnosis; children with autism frequently have low IQ.Similarly characterised behaviour often has a diagnostic overlap with AS.
If the person meets the autistic disorder criteria, then they should be assigned that diagnosis, as per the hierarchy rule. This means that autistic disorder takes priority over AS, such that if an individual meets the criteria for both (which is possible), then they should be given the diagnosis of autistic disorder, not AS.However, specific communication impairments are also needed for a diagnosis.
Pervasive developmental disorder, not otherwise specified (PDD-NOS)
This category is reserved for those who, although presenting with one or more social, communicative, or behavioural impairments, fail to meet the criteria for one of the specific autism spectrum disorders (ASDs).
PDD-NOS is easily differentiated from AS on the basis of whether the threshold number of diagnostic items is reached. Diagnosis is made clinically, and is essentially reserved for individuals who have the social impairments seen in other ASDs, but do not meet all the essential criteria for any of the specific disorders.
Schizoid personality disorder
Social aloofness, emotional coldness, and preoccupation with fantasy and introspection.Later onset compared with AS and lack of obsessive pursuit of circumscribed interests.
Schizoid personality disorder is differentiated from AS during the clinical interview on the basis of, 1) social aloofness, 2) later onset, and 3) lack of ritualistic or repetitive patterns of behaviour.
Social anxiety disorder
Social phobia onset can be clearly described: physical symptoms of anxiety in social situations that result in avoidance. Social anxiety generally improves with treatment.
Social anxiety should be suspected in any person who describes a clear onset of somatic anxiety symptoms in social situations, but whose social and behavioural development is otherwise inconsistent with AS.
Non-verbal learning disability (NLD)
NLD is the term used to describe the clinical picture of children who have significant impairments of non-verbal aspects of cognition (which include perceptive, visuospatial, and non-verbal-based reasoning abilities), while retaining normal aspects of verbal cognition (such as phonology, verbal reception, and verbal repetition). Strikingly, such children have a pattern of socio-communicative vulnerabilities resembling those seen in AS. They exhibit impairment of social perception and judgement, and thereby social interaction, and tend to rely on rote-learned information, thereby coping poorly with novel situations.
Interestingly, a similar pattern of cognitive strengths and vulnerabilities has also been recorded among children with AS. The nosological validity of NLD compared with AS has not been established, and so the use of this term diagnostically is not encouraged.This is a diagnosis based on the individual's pattern of verbal and performance IQ scores. If diagnosis for AS is met, this should be made as the preferred diagnosis.
Semantic pragmatic disorder
Everyday use of language (pragmatics) is impaired, but formal language skills are intact. This manifests as poor ability to construct conversational texts, to presuppose others' knowledge, and to understand others' communicative exchanges (beyond literal meaning).
This is a diagnosis based on the individual's pattern of communicative strengths and vulnerabilities. However, with its diagnostic validity being poorly established, if criteria for a diagnosis of AS are met, this should be made as the preferred diagnosis.
Attention deficit hyperactivity disorder (ADHD)
Individuals with ADHD may have associated difficulties with social interaction and communication as a result of their primary disturbance of attention and concentration, and motor dyscontrol. They often talk excessively and show difficulty waiting their turn.
A diagnostic interview will differentiate between ADHD and AS.
Bipolar disorder
Bipolar disorder is characterised by symptoms of depression and symptoms of mania. Manic symptoms include a persistently elevated, expansive, or irritable mood; decreased sleep; very rapid speech; and excessive pursuit of pleasurable activities despite negative consequences.
A diagnostic interview will differentiate between bipolar disorder and AS.
Obsessive-compulsive disorder (OCD)
Differentiating from OCD carries particular difficulties, but it must be remembered that many of the repetitive patterns of behaviour among individuals with AS are ego-syntonic (thoughts, impulses, attitudes, and behaviour are felt to be acceptable and consistent with the total personality), whereas in OCD they are characteristically ego-dystonic (elements of a person's behaviour, thoughts, impulses, drives, and attitudes are unacceptable to them and cause anxiety). The repetitive patterns of behaviour are integral to the disorder.
Meets the DSM-IV-TR (or ICD-10 criteria) diagnostic criteria for OCD.

Aspergillosis

Mucormycosis and other zygomycoses (e.g., phycomycosis, basidiobolomycosis)
Paranasal sinuses and pulmonary symptoms are more common.Presence of black necrotic lesions of the nasal mucosa and hard palate.Rapid spread of involvement without regard to anatomical plane, with hypo-aesthetic skin patches.Zygomycoses are common in patients with (poorly controlled) diabetes with sino-orbital or rhinocerebral involvement.
Culture and histopathology of tissue and specimens. [81] While Zygomycetes appear as broad, non-septate hyphae with branches occurring at right angles, Aspergillus appears as narrower, septate hyphae with frequent acute-angle branching. Often, these 2 entities may be difficult to distinguish. Blood cultures are negative in zygomycosis as with aspergillosis.No serological test is available.Radiological appearance is similar to that of aspergillosis.
Fusariosis
Common in patients with severe, prolonged neutropenia; the disease may begin at a site of trauma or with onychomycosis.Fever and myalgia are common.Skin lesions occur in 60% to 80% of infections.Less commonly, other filamentous fungi may produce lesions indistinguishable from aspergillosis.
Blood cultures are frequently positive. [82]Tissue cultures help to distinguish the pathogens; histologically Fusarium resembles Aspergillus.No serological test is available.Radiological features and host characteristics are similar to those of aspergillosis. [82]
Scedosporiosis
May involve lungs, bones, joints, and CNS.In the compromised host, fever, erythematous raised lesions involving the skin, and brain involvement are common.Less commonly, other filamentous fungi may produce lesions indistinguishable from aspergillosis.
Tissue cultures help to distinguish the pathogens; histologically, Scedosporium resemble Aspergillus.No serological test is available.Radiological features and host characteristics are similar to those of aspergillosis. [82]
Nocardiosis
No differentiating signs or symptoms.
As the host characteristics and clinical/radiological features are similar, culture/histology of the lesion (skin, lung nodule, brain mass/abscess) is required for diagnosis. [83] Histologically, Nocardia appears as gram-positive, branching, slender, filamentous organisms (acid-fast smear positive). Not infrequently, respiratory secretions or aspirate from abscess may reveal the organism.Rarely, standard blood cultures are positive with prolonged incubation.
Mycobacterial infection
Cough, sputum production, and fever may be prominent.Country of origin and contact hx for tuberculosis may increase suspicion for Mycobacterium tuberculosis infection.Atypical Mycobacteria, such as Mycobacterium avium, may present with respiratory symptoms, particularly in patients with chronic lung disease.
Nodules and cavities on CXR or chest CT scan may be seen.Respiratory secretions (sputum, bronchoalveolar lavage (BAL) fluid) are helpful for diagnosis.Occasionally, biopsy of involved lungs for mycobacterial stain and culture is needed.
Pneumonia
Due to bacteria such as Pseudomonas aeruginosa, may present with clinical features similar to those of aspergillosis.Fever, sputum production, cough, and shortness of breath are prominent.
Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.Blood cultures may be positive.CT-guided needle aspiration of the pulmonary lesion may be required for diagnosis.
Endocarditis
Systemic bacterial infections may secondarily involve the lung and present with features of pneumonia.
Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.Blood cultures may be positive.CT-guided needle aspiration of the pulmonary lesion may be required.
Sepsis
Systemic bacterial infections may secondarily involve the lung and present with features of pneumonia.
Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.Blood cultures may be positive.CT-guided needle aspiration of the pulmonary lesion may be required.
Pulmonary embolism
Underlying predisposing condition such as immobility/prolonged bed rest, hypercoagulability, or venous thrombosis of the lower extremities/pelvis.Pleuritic chest pain and shortness of breath may be the dominant symptoms. Fever, cough, and sputum production are less common. Pleural rub may be present.
CXR or chest CT scan of chest typically shows wedge-shaped, peripheral pulmonary emboli/infarcts, at times mimicking findings of aspergillosis; however, multiple nodules, 'halo sign', and cavities are generally not seen.
Malignancy
Lymphoma involving the lung, and other malignancies, primary or metastatic in lungs, may mimic pulmonary aspergillosis. Clinical features may be indistinguishable.
Comparison of serially obtained CXR/CT scans of chest is extremely helpful to distinguish pre-existing malignancy from recent pulmonary aspergillosis.Biopsy of the lesion is required for definitive diagnosis.Anecdotal data suggest that PET-CT scan may be useful to distinguish malignancy from an opportunistic process.
Allergic bronchopulmonary aspergillosis
Hx of allergic asthma, hx of cystic fibrosis; increased shortness of breath and wheeze
CXR is usually undertaken early in the work-up of chest symptoms. Skin testing, serology testing, and high-resolution CT of the chest are usually performed.

Aspiration pneumonia

Aspiration (chemical) pneumonitis
Occurs immediately after the precipitating event.Clinically difficult to distinguish. Symptoms persist beyond the initial 24 hours. Similar pulmonary signs are seen such as coughing, wheezing, cyanosis, hypoxaemia, pulmonary oedema, respiratory distress, or gastric contents in oropharynx.Cardiac signs such as hypotension are also similar.
Sputum Gram stain shows no WBCs.
Atelectasis
Depends on the size of area of lung that is affected and speed at which lung collapse occurs. If a large area of the lung is affected with rapid onset, there is typically pain on the affected side, dyspnoea (sudden onset), and cyanosis. Slower onset of lung collapse may be asymptomatic or cause only minor symptoms. A harsh, non-productive cough is produced by gradual collapse of the right middle and lower lobes.
Lack of leukocytosis, or other markers of active infection. CXR usually shows changes in posterior dependent aspects.
Pulmonary oedema
Presents with SOB, fatigue, dyspnea on exertion and tachypnea. History of heart disease or fluid overload can usually be elicited.Crackles are heard on auscultation.
CXR typically shows symmetric distribution of opacities, although may not be evident early on. Evaluation of left ventricular dysfunction by BNP and echo are helpful.Leukocytosis usually not present.
Lipoid pneumonia
Form of aspiration pneumonia occurring acutely or chronically from aspiration of vegetable fat or mineral oil (exogenous form). There is a history of ingestion of lipid over periods of time. Acute form may present with fever and cough especially in younger patients. Chronic form may be asymptomatic.
CT can occasionally demonstrate low attenuation areas (-30HU).
Community-acquired pneumonia (CAP)
Patients typically complain of productive cough, breathlessness, chest or abdominal pain, fever, and general malaise. Older people present with atypical symptoms including confusion, lethargy, and general deterioration.
Common organisms detected on sputum culture are Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Klebsiella pneumoniae, and other gram-negative bacilli.Atypical organisms may be detected with appropriate testing (e.g., serology or antigen tests).
Hospital-acquired pneumonia (HAP)
Green-yellow sputum.No difference in signs and symptoms. HAP refers to any pneumonia that develops after 72 hours of hospitalisation. This includes all types of pneumonias, including aspiration pneumonia.
Sputum culture showing growth of gram-negative rods or Staphylococcus aureus is more likely.

Asthma in adults

Cystic fibrosis
Chronic, sometimes productive cough with a possible family history of CF.Nasal polyposis at or before 12 years of age and symptoms related to other organ involvement, such as diarrhoea, malabsorption, or failure to thrive.
Sweat chloride testing: level of sweat chloride >67 mEq/L.Consider repeat testing.
Chronic rhinosinusitis
May present with nocturnal cough and dyspnoea from post-nasal discharge.May co-exist with asthma.
Anterior rhinoscopy or nasal endoscopy may show inflammation, purulent discharge, oedema, or frank polyps.CT may show opacification of involved sinuses, mucosal thickening, air-fluid levels, or anatomic abnormalities.
Tracheomalacia
Symptoms are usually positionally dependent and occur within the first weeks or months of life.Expiratory stridor and a barking brassy cough, wheezing respiratory distress with additional breath sound at the end of expiration (the bagpipe sign) are accompanied by the occasional extension of the neck with breathing, inspiratory stridor, episodes of holding of breath, anoxia, recurrent respiratory infections, retraction of intercostal and subcostal muscles, failure to thrive, and respiratory and cardiac arrest. [41]
The sensitivity of plain x-rays is 62%, using microlaryngoscopy and bronchoscopy as the reference standards.In addition to CXR, barium oesophagography is useful for evaluating associated disease processes, such as tracheo-oesophageal fistula and reflux disease.
Vascular ring
Wheezing, shortness of breath, occasional stridor.
CT chest with contrast: double aortic arch, abnormal take-off of the innominate artery, anomaly of left pulmonary artery, right aortic arch, aberrant right subclavian, enlarged pulmonary veins. [41]
Foreign body aspiration
Wheezing, shortness of breath, occasional stridor are common.If the foreign body is in the peripheral airway, localised one-sided wheezing or collapse of the distal lung tissue is found.
CXR, CT chest, or bronchoscopy shows the foreign body.
Vocal cord dysfunction
Inspiratory and expiratory wheezing is often difficult to differentiate.Should be considered in steroid-resistant asthma patients, but may be co-existent with asthma.
Direct visualisation of the vocal cords with rhinolaryngoscopy during a spell. Inspiratory flow volume loop is helpful when abnormal (flattened).
Alpha-1 antitrypsin deficiency
Wheezing, resistant to management.May have family history of parents or grandparents dying of lung disease.
Testing for the alpha-1 antitrypsin phenotype.
COPD
History of smoking.Dyspnoea occurs with or without wheezing and coughing.Examination may show barrel chest, hyper-resonance to percussion, and distant breath sounds.
PFTs with residual volume (RV), total lung capacity (TLC), and a flow volume loop with bronchodilator showing an obstructive pattern with an increase in TLC and RV and a reduction in forced expiratory flow at one second (FEV1), FEV1/forced vital capacity (FVC) ratio with no response to bronchodilator.CXR showing hyper-inflation of the lungs.
Bronchiectasis
Dyspnoea, cough, and wheezing and, if severe, recurrent pulmonary infections.
High-resolution CT chest: dilated airways, bronchial wall thickening.Can occasionally be seen on CXR.
Pulmonary embolism
Patients have a wide variety of presentations but most common is shortness of breath and pleuritic pain.
Pulmonary angiogram is the preferred test, but carries risks.An acceptable alternate test is CT angiogram of the lung, which, if not available, can be replaced with the less sensitive V/Q scan.
Congestive heart failure
History of CAD or uncontrolled HTN.Exam shows dependent oedema, elevated jugular venous pressure, and basal pulmonary crepitations.
CXR may show increased alveolar markings, fluid in fissures, and pleural effusions.Echocardiogram: reduced left ventricular ejection fraction.
Common variable immunodeficiency
History of recurrent, usually sinopulmonary, infections.
Serum IgG level <5g/L (500 mg/dL).

Asthma in children

Viral-induced infantile wheezing
Onset in infancy. No associated atopy. Associated with maternal smoking. Retrospective diagnosis made once the child has left the infantile age range.
Non-atopic result on skin prick testing may provide supportive evidence, but this is not definitive. Causes include respiratory syncytial virus and parainfluenza viruses. [15]
Episodic (viral) wheeze
Wheeze triggered only by viral infections.
None reliable.Data shows that the new classification of recurrent wheeze may fluctuate during the preschool years. [47] [48]
Inhaled foreign body
History of sudden onset of symptoms such as cough, wheeze, or choking is suggestive. Differential air entry or wheeze exists on auscultation. Chronic symptoms include recurrent episodes of wheeze.
Inspiratory and expiratory chest radiographs may reveal asymmetry of chest expansion due to the 'ball-valve' mechanism of the foreign body. Chronic changes include collapse and consolidation distal to the obstruction.Bronchoscopy is necessary for confirmation of the diagnosis and retrieval of the foreign body.
Recurrent aspiration
History of vomiting may be present. Gastro-oesophageal reflux and swallowing incoordination are risk factors. Focal signs of pneumonitis or pneumonia may be present on examination acutely during episodes. Chronic aspiration may be complicated by development of bronchiectasis (suggested clinically by localised crepitations, decreased air entry, and clubbing).
Focal signs of pneumonitis or pneumonia on chest radiography. Chronic changes include those of bronchiectasis (bronchial wall thickening and dilatation).
Cardiac failure
Other features of cardiac failure are present (tachycardia, gallop rhythm, or hepatomegaly). Associated with congenital or acquired heart disease.
Cardiomegaly and pulmonary oedema may be present on chest radiography.
Cystic fibrosis (CF)
Airway inflammation associated with CF may precipitate wheeze, cough, and respiratory distress. CF due to milder mutations may present with difficult-to-control asthma. Asthma may coexist with CF. Failure to thrive may be present.
Sweat test: sweat chloride 60 mmol/L or greater (60 mEq/L or greater) on repeat samples is diagnostic (levels of 40-59 mmol/L should be considered as indeterminate and suspicious). [49]
Primary ciliary dyskinesia
Associated with neonatal respiratory distress and recurrent childhood otitis media and sinusitis.50% have situs inversus (Kartagener's syndrome).Chronic moist cough. Important differential to consider in difficult-to-manage chronic asthma.
Ciliary studies (light and electron microscopy) reveal abnormal ciliary movement and structure.Situs inversus (dextrocardia and abnormally situated gastric bubble) may be present on standing chest x-ray.
Tracheomalacia
Characterised by expiratory stridor or monophonic expiratory wheeze. Recurrent acute episodes of stridor, wheeze, dyspnoea, or cough usually present during the first 2 years of life.
Bronchoscopy demonstrating collapse of the trachea during expiration.
Bronchomalacia
Characterised by expiratory stridor or monophonic expiratory wheeze. Recurrent acute episodes of stridor, wheeze, dyspnoea, or cough usually present during the first 2 years of life.
Bronchoscopy demonstrating collapse of the bronchus during expiration.
Recurrent protracted bronchitis
Bronchitis is characterised by moist cough in combination with wheeze, and may be caused by bacterial or viral infection. Bacterial cause is suggested by purulent sputum and response to adequate antibiotic course. [50]
In bacterial bronchitis the sputum culture will most commonly isolate Haemophilus influenzae or Streptococcus pneumoniae. [51]
Vocal cord dysfunction
Paradoxic adduction of the vocal cords during inspiration resulting in high-pitched inspiratory stridor and dyspnoea that may be misinterpreted as wheeze. An expiratory component may be present. Typically loudest over the central airways. May be spontaneous or exercise-induced.
Exercise testing may reproduce the characteristic symptoms.Spirometry during an episode demonstrates blunting of inspiratory volume loop.
Hyperventilation
More common in later childhood or adolescence. Associated with anxiety. No associated wheeze on auscultation and good air entry.
No obstructive pattern on spirometry during a hyperventilation episode.
Exertional dyspnoea
Perception of breathlessness during exercise alone.
Exercise testing may help distinguish.

Astigmatism

Myopia
Any uncorrected myopia can cause reduced visual acuity and should, therefore, be included in the differential diagnoses of blurred vision. It is impossible to distinguish the different causes of blurred vision by history taking and visual acuity testing alone. [33]
Retinoscopy can easily distinguish between simple myopia, in which neutralisation of the reflex is obtained in all meridians by the same dioptric power, and astigmatism, where different dioptric powers are required in different meridians. [24]
Hyperopia
Any uncorrected hyperopia can cause reduced visual acuity and should, therefore, be included in the differential diagnoses of blurred vision. It is impossible to distinguish the different conditions merely by history taking and visual acuity testing. [33]
Retinoscopy can easily distinguish between simple hyperopia, in which neutralisation of the reflex is obtained in all meridians by the same dioptric power, and astigmatism, where different dioptric powers are required in different meridians. [24]
Cataract
Cataract is characterised by painless, progressive blurred vision, but it is also associated with other complaints such as difficulty seeing in bright sunlight and glare from incoming headlights at night, which are not common in astigmatism. [34]
Cataract can be easily diagnosed and graded using slit lamp biomicroscopy. The presence of cataract does not rule out co-existing astigmatism and therefore refraction also should be determined. [34]
Strabismus
Certain types of strabismus are associated with diplopia, which may be interpreted as blurred vision. In some cases, but not all, the misalignment of the eyes is obvious to the observer or is reported by the patient's relatives. [34]
Strabismus can be diagnosed by cover-uncover test, in which an occluder is used for alternate covering of the eyes in order to detect an obvious or a hidden eye deviation. The presence of strabismus does not rule out co-existing astigmatism, and therefore refraction should also be determined. [34]
Age-related macular degeneration (AMD)
Gradual blurring of vision in person >50 years old must raise the suspicion for AMD. As the degeneration progresses, the patient may also complain of metamorphopsia (straight lines appear curved or wavy) and scotomas. [34]
The diagnosis can be achieved by a thorough fundus examination and confirmed by fluorescein angiography. [34]

Astrocytic brain tumours

Brain metastasis
May or may not have systemic disease and/or known history of cancer.Systemic symptoms include cachexia, respiratory problems, haemoptysis, chest pain, and bone pain.
MRI: typically, more localised lesions that may be multiple, and with proportionally more vasogenic oedema.Chest-abdominal CT scan, bone scan, and PET scan provide evidence of systemic disease.Histology provides a definitive diagnosis.
Brain abscess
May or may not have systemic symptoms such as fever, cachexia, and chills.Risk factors differ and may include pulmonary abnormalities, congenital cyanotic heart disease, bacterial endocarditis, and penetrating head injury.
MRI demonstrates a thinner capsule toward the ventricle, with restricted diffusion of pus and elevated lactate level; may show multiple lesions.Blood tests suggestive of infection: for example, elevated WBC count, elevated erythrocyte sedimentation rate (ESR), and elevated C-reactive protein (CRP), with sensitivity 90% and specificity 77%. [31]Biopsy or aspiration provides the definite diagnosis, demonstrating pus (inflammatory cells), no tumour cells, and a positive culture of bacterial agent or fungus.
Multiple sclerosis
Typically presents in women aged 20 to 40 years, with acute neurological symptoms that wax and wane (dissemination in space and time): for example, optic neuritis, transverse myelitis (spinal cord symptoms), and focal neurological symptoms.
MRI shows multiple lesions in the periventricular white matter; may or may not enhance.CSF shows oligoclonal bands.Histology provides the definitive diagnosis, demonstrating demyelinating lesions, inflammatory cells, and absence of tumour cells, but usually is not necessary.
Necrosis
Known brain tumour treated with radiotherapy in the past.May present with progressive neurological symptoms or no symptoms at all.
PET scan is cold.Histology provides definitive diagnosis (no tumour cells and extensive necrosis).
Acute stroke
Acute onset of neurological symptoms.Often in older patients with cardiovascular risk factors.Rarely present with seizures (3% to 5% only).
MRI shows typical vasculature distribution and restricted diffusion.
Encephalitis
Systemic symptoms present (fever and cachexia).
CSF shows leukocytosis, Herpes simplex virus (HSV) antibodies, and/or RBCs.EEG is characteristic with periodic lateralising epileptiform discharges.CT or MRI shows oedematous temporal lobes and haemorrhagic transformation.Brain biopsy is definitive with virus isolation.
Oligodendroglioma
No specific difference in clinical presentation except that oligodendrogliomas are more prone to present with seizures.
CT scan demonstrates calcification in 90% of cases.Cortical location on MRI.Histology provides definitive diagnosis with classic fried egg cytoplasm and chicken wire vasculature.
Dysembryoplastic neuroepithial tumour
Typically occurs in patients <20 years of age and presents with chronic seizure disorder.
MRI demonstrates a cortical lesion with distinct margins.CT may show deformity over the calvaria.Histopathology provides definitive diagnosis.
Ganglioglioma
Presents in the first 2 or 3 decades of life with seizure disorder.
MRI commonly demonstrates medial temporal lobe lesion with cystic components and/or calcifications.Histology is definitive with characteristic cell types: ganglion and glial cells.

Atopic dermatitis

Seborrhoeic dermatitis
Characteristic greasy scale that is not pruritic. Often affects cheeks on face, scalp, extremities and trunk. Unlike atopic dermatitis, the nappy area is often affected.
Clinical exam is the best tool to differentiate between these lesions.
Irritant contact dermatitis
Common in nappy area, face, and extensor surfaces in children resulting from exposure to irritating substances. Typically less pruritic than atopic dermatitis.
Elimination of irritant will result in clinical improvement.Patch testing may be positive for relevant irritant.May be limited role for skin biopsy (e.g., patch tests are negative, chronic disease, uncertain diagnosis), which can identify whether contact dermatitis is present, but does not distinguish irritant from allergic contact dermatitis.
Allergic contact dermatitis
Well-circumscribed erythematous lesions, often with spongiotic papules, vesicles, and crusting. Lesions are usually pruritic. Eruptions are due to contact with specific allergen, and removal of offending agent results in resolution of symptoms.
Elimination of allergic stimuli results in resolution of dermatitis.Patch testing may be positive for relevant allergen.May be limited role for skin biopsy (e.g., patch tests are negative, chronic disease, uncertain diagnosis), which can identify whether contact dermatitis is present, but does not distinguish irritant from allergic contact dermatitis.
Scabies
Severe pruritus, particularly at night. In addition to papules or vesicles, burrows may be evident and will help to make the diagnosis. The wrists, ankles, palms, soles, interdigital spaces, axilla, waist and groin are the most commonly affected sites. Patients will often report similar symptoms in family members or other close contacts. [3]
Microscopy may reveal mites, eggs or scybala (mite faeces).
Psoriasis
Well-circumscribed, erythematous lesions with silver scale that show a predilection for extensor surfaces, particularly elbows and knees. The nail pitting seen in psoriasis has smaller pits and is more common than that seen in patients with atopic dermatitis.
This is usually a clinical diagnosis. No laboratory testing is typically necessary to distinguish between atopic dermatitis and psoriasis. If the diagnosis is uncertain, there may be a limited role for skin biopsy which may not always reveal the classic features of psoriasis.
Mycosis fungoides
The initial stages of mycosis fungoides (cutaneous T cell lymphoma) may look similar to atopic dermatitis. Erythematous plaques in random distribution are common and scale is often present. As opposed to patients with atopic dermatitis, patients with mycosis fungoides tend to be older at the time of diagnosis, with an average age of 50 years.
Skin biopsy is necessary to make the diagnosis of mycosis fungoides.

Atrial flutter

Atrial fibrillation
none
ECG shows uncoordinated atrial activation with rapidly oscillating, fibrillatory waves that vary in amplitude, shape, and timing. [7]
Atrial tachycardia
none
Generally, by ECG, atrial tachycardia has isoelectric intervals between the P waves in all leads. At very high atrial rates, it may be extremely difficult to distinguish the two. [7]

Atrial myxoma

Mitral stenosis
There may be no differences in symptoms and signs.
ECG will most frequently reveal left atrial hypertrophy. Echocardiogram will show stenosis of the mitral valve.
Infective endocarditis
Syncope is unusual as a presenting symptom in infective endocarditis. Patients with endocarditis may have a fever, petechiae, splenomegaly, history of drug abuse, previous endocarditis, or prosthetic valves. Otherwise there may be no major differentiating symptoms and signs.
Echocardiogram will reveal the valvular vegetation. Blood culture indicates the causative organism.
Atrial thrombus
There may be no differences in symptoms and signs. View imageView image
Echocardiogram or MRI/CT scan will reveal the thrombus. Echocardiogram will also identify the catheter that is commonly associated with the formation of the thrombus. Rarely a transvenous biopsy may be indicated.
Connective tissue disease
Symptoms of arthralgia and fatigue, and peripheral signs of vasculitis. Syncope and acute heart failure are unusual presenting features.
Specific ANAs in the blood may identify the disease process. ECG findings in connective tissue disease are non-specific with no differentiating features.
Other cardiac tumour
There may be no differences in symptoms and signs.
Imaging studies (e.g., CT scan and MRI) will reveal cardiac tumour.

Atrial septal defects

Partial anomalous pulmonary venous drainage
Signs and symptoms similar to atrial septal defect
Atrial septum intact with dilated right heart structures: identified by echocardiography in children, and MRI or CT in adults.
Ventricular septal defect
Small ventricular septal defects (VSDs) are associated with a holosystolic murmur and normal first and second heart sounds. With a larger shunt volume (ratio of pulmonary to systemic blood flow, Qp:Qs, >2), a mid-diastolic mitral valve flow murmur may be heard in addition to a holosystolic mid-frequency murmur.
VSD identified by Doppler echocardiography.
Patent ductus arteriosus
Associated with prematurity. Patent ductus arteriosus is also associated with bounding peripheral pulses due to wide pulse pressure. The left ventricular impulse may be prominent. The murmur associated with a patent ductus arteriosus is often described as a machinery-like continuous murmur. However, in some premature and newborn infants the murmur can be heard only in systole. A mid-diastolic mitral valve flow murmur may be heard.
PDA identified by Doppler echocardiography.
Pulmonary stenosis
A click follows the first heart sound, which is best heard at the left upper sternal border.The second heart sound may be normal, split, or single depending on the severity of the stenosis.
Pulmonary stenosis identified by Doppler echocardiography.
Right bundle-branch block
Can produce a widely split second heart sound similar to that heard in patients with an ASD.The characteristic ASD murmurs are absent.
ECG shows right bundle-branch block.Echocardiography shows no evidence of an ASD.
Other congenital heart defects
ASDs occur in the context of other congenital heart conditions, including transposition of the great arteries, pulmonary atresia, and Ebstein's anomaly.
Abnormal anatomy identified by Doppler echocardiography.

Atrioventricular block

Junctional rhythm
In patients with profound first-degree AV block and very long PR intervals, the P wave may encroach so closely on the QRS complexes that they appear to be retrograde P waves, suggesting junctional rhythm. Retrograde P waves in junctional rhythm should be inverted in the inferior leads (II, III, and aVF), whereas in sinus rhythm with profound first-degree AV block, the P waves are upright in those leads.
Comparison of numerous ECGs obtained at different times (i.e., days or months apart) may be useful. Baseline ECGs showing profound first-degree AV block may also help make the diagnosis.
Supraventricular tachycardia (SVT)
In patients with profound first-degree AV block and very long PR intervals, the P wave may encroach so closely on the QRS complexes that they appear to be retrograde P waves, suggesting SVT. Retrograde P waves in SVT are frequently inverted in the inferior leads versus upright in sinus rhythm with first-degree AV block.
Variations in the heart rate and the PR and RP (QRS to P) intervals suggest against the diagnosis of SVT. Comparison of numerous ECGs may be very useful.
Atrial fibrillation or multifocal atrial tachycardia (MAT)
The irregularity of the RR intervals in type I second-degree AV block may lead to the incorrect diagnosis of atrial fibrillation or MAT. The presence of distinct P waves and the grouped pattern of the RR intervals are characteristic of type I second-degree AV block and are not seen in atrial fibrillation or MAT.
Careful inspection of the ECG should allow distinction between these diagnoses.
Sinus rhythm with intact AV conduction
In patients with third-degree AV block, if the rate of the junctional escape rhythm is similar to that of the sinus rate, an appearance of sinus rhythm with intact AV conduction may be possible. In most of these cases, with a long enough rhythm strip, the lack of a relationship between the sinus beats and the QRS complexes will become apparent.
Examination of a long rhythm strip should allow for the correct diagnosis to be made.
Tachy-brady syndrome
The RR intervals are irregular and short, suggesting atrial fibrillation with a fast ventricular rate. At the termination of the tachyarrhythmia, the diseased sinus node is slow to take over, resulting in a pause and a slow ventricular rate.
There is no AV block.View image

Attention deficit hyperactivity disorder in adults

Depression in adults
Significant, sustained depressed mood; loss of interest in usual activities.Excessive guilt.Hopelessness, suicidal ideation.
Diagnosis based on DSM-IV criteria.Medical testing (e.g., CBC, TFTs) is done to exclude causative medical conditions.
Bipolar disorder in adults
Significant mood instability: irritability, euphoria, depression.Rapid speech, increased energy, decreased need for sleep.Poor judgment: spending sprees, hypersexuality, getting into arguments/fights.Delusions (fixed false beliefs)/ hallucinations with more severe illness.Suicidal ideation.
Diagnosis based on DSM-IV criteria.Medical testing (e.g., CBC, TFTs) is done to exclude causative medical conditions.
Generalised anxiety and other anxiety disorders
Excessive worry.Panic states with autonomic arousal.Obsessive thoughts/compulsive behaviours.Muscle tension.
Diagnosis based on DSM-IV criteria.Medical testing (e.g., TFTs) is done to exclude causative medical conditions.
Psychosis
Delusions (fixed false beliefs).Hallucinations (most usually auditory).Odd or strange ideas.Social isolation.
Diagnosis based on DSM-IV criteria.Medical testing is done to exclude causative medical conditions.
Learning disorder
Circumscribed difficulties with reading, mathematics or written expression.Learning problems significantly interfere with academic achievement or activities of daily living.School dropout, poor work performance.
Standardised testing in reading, mathematics or written expression.
Language disorder
Circumscribed difficulties with language expression or comprehension.Language problems significantly interfere with academic achievement or activities of daily living.Limited vocabulary, poorly organised speech.Pronunciation difficulties, stuttering, lisping, erratic speech rhythm.Difficulties understanding words/specific types of words (spatial terms), sentences.
Standardised testing in expressive, receptive language or specialised functional assessment of language abilities.
Mental retardation
Known IQ of 70 or less.Deficits in numerous areas of adaptive functioning: communication, self-care, home living, social/interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health and safety.
IQ testing: score of 70 or less.Adaptive behaviour scales (Vineland Adaptive Behaviour Scales and the American Association on Mental Retardation Adaptive Behaviour Scale).
Seizure disorder
Observer report of sudden loss of consciousness followed by tonic-clonic motor activity.Observer report of altered state of consciousness accompanied by simple or complex motor activity and/or vocalisations.Patient report of loss of consciousness, awakening with muscle aches and/or incontinence.Patient report of periods of lost time, disorientation/confusion.
Brain MRI: usually normal in primary generalised epilepsy; may demonstrate a variety of lesions in partial epilepsy.EEG: during a generalised seizure, EEG demonstrates bilateral synchrony in the epileptiform activity. In partial epilepsy, a focal region of spike and sharp wave activity may be detected interictally.
Traumatic brain injury
Accident/trauma history with head involvement.Headaches.
CT or MRI of the head may miss subtle traumatic brain injuries.Studies have found single photon emission computed tomography to be more sensitive than CT or MRI in the diagnosis of traumatic brain injury. [20]Neuropsychological testing battery.
Medication side effects
Recent initiation of prescribed medication and/or OTC medication use.
Urine and/or serum drug screening positive according to medications administered.Cautions with false-positive and false-negative results.
Substance abuse
Report of recent excessive alcohol use, illicit drug use or misuse of prescribed medications; patients may not be forthcoming in providing history.Accidents, fights.
Urine and/or serum drug screening positive.Caution in interpreting drug screen results as false-positive and false-negatives are not uncommonly encountered. Confirmatory testing with a more sensitive test may be necessary if the initial testing result is suspect.
Sleep disorder
Snoring history (patient or bed partner report).Sudden loss of muscle tone (cataplexy).Leg muscle soreness.Observer report of sleepwalking.
Sleep studies/polysomnography (physiological/ respiratory monitoring, eye movements, EMG, EEG) may show patterns consistent with sleep disorder.

Attention deficit hyperactivity disorder in children

Learning/language disorder
Of note, many ADHD patients have comorbid learning disorders. [20]
Neuropsychological testing: pure learning-disordered patients will struggle with inattention in the subject of their disability (e.g., reading) but perform adequately in other academic areas. In contrast, ADHD patients will often demonstrate inattention regardless of subject.
Oppositional defiant disorder
More hostile behaviour, anger, open defiance (at home and school), openly rebellious. Most behaviours are directed at an authority figure. The diagnosis of ODD is not assigned if symptoms exist along with mood or psychotic disorder. May often precede conduct disorder. [40]Careful history and mental status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist should be considered.
Diagnosis is clinical. The Conners rating scale and the child behaviour checklist both have ODD domains.
Depression
Patients with major depression will report depressed mood for at least 2 full weeks in addition to 4 of the following symptoms: impaired sleep, lack of pleasure in activities, feelings of guilt, low energy, poor concentration, psychomotor slowing, anorexia, suicidal ideation. [1]Careful history and mental status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist should be considered.
No differentiating test.
Bipolar disorder
Bipolar disorder is characterised by symptoms of depression and symptoms of mania. [1]Manic symptoms include a persistently elevated, expansive, or irritable mood lasting at least 1 week and 3 additional symptoms including grandiosity, decreased sleep, very rapid speech, disorganised and rapidly shifting thoughts, increased goal-directed activities, psychomotor agitation, and excessive pursuit of pleasurable activities despite negative consequences.Careful history and mental status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist should be considered.
No differentiating test.
Anxiety
Symptoms of anxiety consist of worries, phobias, obsessions or compulsions, tremor, physiological symptoms (palpitations, shortness of breath, sweating). [1]Careful history and mental status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist should be considered.
No differentiating test.
Psychosis
Psychotic disorders such as schizophrenia include a mixture of positive symptoms (delusions, auditory or visual hallucinations, disorganised speech) and negative symptoms (thought blocking or slowed thinking, flat facial expression) that persist for a significant amount of time during a 1-month period.Psychotic disorders are associated with marked social, academic, or occupational dysfunction. [1]Careful history and mental-status examination with collateral information will help distinguish from ADHD.Referral to a psychiatrist is indicated.
No differentiating test.
Autism spectrum disorder (includes pervasive developmental disorders)
The most striking feature of patients with autism spectrum disorders is impaired social interaction, a restricted range of interests, and difficulty adapting to new situations. Language development is often significantly delayed, though social impairment can be the most prominent delay in Asperger's syndrome. [1]Careful history and mental-status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist, a neurologist, or a developmental paediatrician should be considered.
No differentiating test.
Mental retardation
Defined as an IQ significantly below average (≤70) in addition to significant limitations in adaptive functioning in 2 of the following areas: communication, self-care, home living, social/interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety. [1]Mental retardation can be distinguished from ADHD by its greater impairment in areas other than inattention, hyperactivity, or impulsivity.
Referral to a psychologist for IQ testing.Genetic testing may be performed if there is suspicion of a chromosomal abnormality (e.g., Down's syndrome, fragile X).Imaging, thyroid function tests, and metabolic work-up may help elucidate the cause of the disorder.
Conduct disorder
Conduct disorder is a repeated pattern of violating the rights of others or society's rules. These include 4 main groups of behaviour: aggression that hurts people or animals, destruction of property, lying or stealing, and serious rule violations. [1]Careful history and mental status examination with collateral information will help to distinguish from ADHD.Referral to a psychiatrist should be considered.
No differentiating test.
Lead toxicity
Blood lead level should be obtained in high-risk children such as those living in poverty, recent immigrants, and children with developmental delay. [41]
Blood lead level
Iron deficiency anaemia
Iron deficiency anaemia can lead to pallor, fatigue, irritability, and anorexia. Skin findings include angular stomatitis (cracking at the corner of the mouth), glossitis (tongue inflammation), and spooning of the fingernails. Neurocognitive deficits can also occur and may be irreversible.
FBC will show microcytic anaemia (MCV <80 femtolitres).Iron deficiency can be demonstrated by lower transferrin saturation (serum iron/total iron-binding capacity x 100), lower serum ferritin, or higher soluble transferrin receptor. [42]
Fetal alcohol syndrome
Antenatal exposure to alcohol can have toxic effects on the fetal brain and lead to impaired cognitive development and higher levels of ADHD.In contrast to ADHD, however, patients with fetal alcohol syndrome often have a distinct facial appearance (smooth philtrum, thin upper lip, upturned nose, epicanthal folds) and may have microcephaly and shorter stature. [43]Antenatal history of alcohol exposure can be obtained by screening mothers with the T-ACE questions (tolerance, annoyance, cut down, eye opener). [44]Physical examination can detect facial abnormalities.
No differentiating test.
Neurocutaneous syndromes
These are a group of heterogeneous disorders that cause tumours to develop primarily in the skin and CNS, although they can affect other organs. [45] Diagnosis is based on physical examination as well as neurological work-up, which may include genetic testing and imaging.
Genetic testing and imaging based on possible syndrome.
Hyperthyroidism
People with hyperthyroidism also have other signs of hypermetabolism such as sweating, significant weight loss, palpitations, and frequent bowel movements. [46] History and physical examination can help distinguish.
Free T4 and TSH are obtained for screening.
Auditory or visual impairment
In infants and toddlers, inattentiveness may be secondary to hearing and vision problems.
Referral for auditory and visual testing.
Child abuse or other environmental stressor
Psychosocial deprivation and stress are associated with increased risk of ADHD, but not all abused or neglected children have ADHD. [32] [33] When abuse is suspected, it is critical to screen children separately from their parents. A physical examination may assist in the diagnosis. Child-protection services must be notified and will gather collateral information.
Skeletal survey can help demonstrate signs of physical abuse.
Seizure disorder
Absence seizures can lead to episodic impairment of attention and focus.History can help distinguish from ADHD.
EEG.
CNS infection/trauma
People who have had a traumatic brain injury often have acute symptoms and long-term impairments that vary by the region of injury.Those who have acute CNS infections will display altered mental status and may have delirium, headache, and fever.
LP, head imaging.
Medication adverse effects
Certain medications can have cognitive adverse effects and this can be recognised by reviewing the medication list for suspect medication (e.g., antihistamines, sympathomimetics, benzodiazepines, carbamazepine, theophylline, and phenobarbital).
Serum levels of some medications can be obtained (e.g., carbamazepine, theophylline, and phenobarbital).
Substance abuse
Intoxication or withdrawal from substances can mimic some of the hyperactivity, impulsivity, and inattentiveness of ADHD. ADHD typically has onset before 7 years of age and is present throughout development and even into adulthood, while experimentation with substances occurs generally in adolescence and adult life. Careful history and physical examination can distinguish isolated substance abuse from ADHD, although the two are often comorbid.
Urine and serum toxicology screens.
Sleep disorder
Sleep disorders affect 25% to 50% of children with ADHD, so it is difficult to distinguish a sleep disorder from ADHD with sleep problems. People with sleep disorders can be inattentive or hyperactive. [47]A careful sleep history including review of time to sleep onset, awakenings at night, and sleep hygiene may identify a sleep disorder.
Sleep studies can give a more definitive diagnosis.

Atypical pneumonia

Typical bacterial pneumonia
Acute onset with a chill followed by a high fever and pleuritic chest pain suggests pneumococcal pneumonia.
Sputum cultures and blood cultures may be positive for Streptococcus pneumoniae or other bacterial pathogens.
Viral pneumonia
Symptoms of dry cough, fever, myalgia, and malaise, which are clinically difficult to differentiate from atypical bacterial pneumonia.
Nasopharyngeal viral cultures may be positive. Relative lymphocytosis on FBC may be detected.
Tuberculosis
A history of immunosuppression or prolonged course that is not responding to antibacterial therapy suggests tuberculosis.
Sputum cultures and acid fast bacilli stains positive. A cavity on the CXR may be observed.
Fungal pneumonia
Travel or exposure in endemic area.There may be extrapulmonary symptoms, for example, rheumatological.
Sputum culture and stain may demonstrate hyphae or yeasts.Antigen detections assays or PCR may identify specific mycoses, for example, aspergillosis.
Pneumocystis pneumonia (PCP)
History of HIV or risk factors should raise suspicion of PCP.
Special stain of sputum or bronchoalveolar lavage for PCP will be positive.
Pulmonary embolism
Absence of fever and/or lack of response to antimicrobial therapy support a diagnosis of pulmonary embolism.
The ventilation-perfusion scan will be positive in pulmonary embolism.
Inhalation/occupational lung injury
A history of exposure to chemicals or special work conditions should raise suspicion of inhalation/occupational lung injury.
Cultures will be negative. There may be diffuse disease on the CXR.
Anthrax
Course of disease may be rapid with respiratory problems; might present with mediastinal masses. Clusters of cases may occur.
Cultures will be positive for Bacillus anthracis. Mediastinal widening may present in the respiratory forms of the disease.
Plague
Course of disease may be rapid with respiratory problems; might present with mediastinal masses. Clusters of cases may occur.
Cultures will be positive for Yersinia pestis. CXR will show unilateral or bilateral consolidation or alveolar infiltrates.
Tularaemia
Course of disease may be rapid with respiratory problems; might present with mediastinal masses. Clusters of cases may occur.
Cultures will be positive for Francisella tularensis. Hilar adenopathy may present in the respiratory forms of the disease.

Autism

Atypical autism (or autistic spectrum disorder [ASD] or pervasive developmental disorder not otherwise specified [PDDNOS])
Children have an autistic spectrum disorder (ASD), but do no't meet ICD-10 or DSM-IV criteria for autism (e.g., children might not have language delay, or have significant enough social communication difficulties to meet criteria for the core disorder).
The clinical history, standardised interview, and observational tools help a clinician come to a conclusion about whether a child has autism, or another form of ASD.
Asperger's syndrome
People with Asperger's syndrome have social, communication, and repetitive domain difficulties but have no language delay and have average or above average IQ.Asperger's syndrome tends to be associated with age-appropriate language abilities (although language is usually used in an unusual way, for example, precise, pedantic speech).
The clinical history, standardised interviews, and observational tools help a clinician come to a conclusion.
Other causes of learning difficulties/mental retardation
Patients do not seem to the specialist to meet criteria for autism, autism spectrum disorder, or Asperger's syndrome and may have one of many other neurodevelopmental disorders underlying their difficulties.In some children, a unifying diagnosis cannot be identified.
The clinical history, standardised interviews, and observational tools help a clinician come to a conclusion.
ADHD
Patients have problems with attention and hyperactivity.Children do not have the same degree of social communication difficulties as children with autism.The early developmental history is of hyperactivity rather than features of autism
The clinical history, standardised interviews, and observational tools help a clinician come to a conclusion.

Autoimmune hepatitis

Primary biliary cirrhosis
Main complaints are fatigue and pruritus, which are usually more pronounced than in AIH.
Alk phos and gamma-GT raised more strikingly than aminotransferase levels. Anti-mitochondrial antibodies (AMAs) present in 95% of cases and ANAs in up to 70%.Liver biopsy shows bile duct lesion or periductal fibrosis.
Primary sclerosing cholangitis
Features often overlap with AIH.More common in men than in women. Median age at diagnosis is approximately 40 years; rare in children.Strongly associated with inflammatory bowel disease.
Markedly raised alk phos. Perinuclear anti-neutrophil cytoplasmic auto-antibodies are dominant auto-antibodies.Abnormal cholangiogram.Liver biopsy shows bile duct abnormalities.No response to corticosteroids.
Chronic hepatitis B
Clinical presentation sometimes similar with mild elevations of LFTs.
Presence of hepatitis B serological markers: HBsAg, antibody to hepatitis B surface antigen, antibody to hepatitis B core antigen, hepatitis B e-antigen, and antibody to hepatitis B e-antigen.Histology: ground-glass hepatocytes; immunoperoxidase staining for hepatitis B virus antigens.
Chronic hepatitis C
Clinical presentation sometimes similar with mild elevations of LFTs.
Presence of hepatitis C serological markers (anti-hepatitis C virus, hepatitis C viral RNA). ANA, smooth muscle antibody (SMA), and anti-liver kidney microsome antibodies (anti-LKM-1) occasionally present.Histology: ground-glass hepatocytes; nodular-appearing infiltrates; steatosis in hepatitis C virus genotype 3.
Chronic hepatitis D
Clinical presentation may be similar. It occurs only in the presence of hepatitis B infection.
Presence of hepatitis B virus and hepatitis D virus serological markers.
Hepatitis due to other viruses
Clinical presentation sometimes similar, with signs of involvement of other organs.
Presence of serological markers of viral infection (CMV, EBV).
Chronic drug-induced hepatitis
History of precipitating drug, for example, methyldopa, minocycline, nitrofurantoin, diclofenac, phenytoin, propylthiouracil.Clinical presentation similar to AIH; female preponderance.
Auto-antibodies (ANA, SMA, anti-LKM) and hyperglobulinaemia also sometimes present.Histological features sometimes consistent with AIH.
Genetic haemochromatosis
Patients usually present with hepatomegaly, abdominal pain, and darkened skin pigmentation. As the iron deposits continue in other tissues (pancreas, heart, and pituitary) leading to progressive damage and dysfunction, additional complications may ensue (diabetes, dysrhythmias, cardiomyopathy, and haemolytic anaemia).
Increased hepatic iron concentrations and raised serum ferritin levels.Genotyping: C282Y homozygosity or C282Y/H63D compound heterozygosity.Histology: qualitative and quantitative hepatic iron determination.
Alpha-1-antitrypsin deficiency
Clinical manifestations related to the lung, the liver, and, much less often, the skin.
Diagnosis of severe alpha-1-antitrypsin deficiency is confirmed by a serum level below 9.2 to 14.7 micromol/L (50 to 80 mg/decilitre) in combination with a severe deficient genotype, generally determined by isoelectric focusing.
Wilson's disease
Symptoms originating from liver or CNS (neuropsychiatric disease). Sometimes cardiac manifestations (arrhythmias).Kayser-Fleisher rings usually present, sometimes skin pigmentation and bluish discolouration at the fingernail base.
Reduced serum ceruloplasmin levels (<200 mg/L (20 mg/decilitre)) in a patient who also has Kayser-Fleischer rings is considered to be diagnostic.Additional findings: serum copper decreased with excessive urinary copper excretion.
Cholangiopathy related to AIDS
Typical symptoms include RUQ and epigastric pain and diarrhoea; fever and jaundice are less common, occurring in 10% to 20% of patients.
LFTs usually indicative of cholestasis. Serological evidence of HIV infection. CD4 count below 100/mm^3.Ultrasound: cholangitis. Diagnosis is made by ERCP.
Non-alcoholic steatohepatitis
Presence of 1 or more components of metabolic syndrome: obesity, diabetes, hyperlipidaemia, hypertension.
ANA sometimes present; other auto-antibodies absent.Magnitude of fatty infiltration, presence of PMN leukocytes, and central fibrosis in the liver biopsy point to steatohepatitis.
Alcoholic liver disease
Similar presentation with chronic elevation of aminotransferases and similar symptoms.History of excessive alcohol drinking.
Auto-antibodies absent. Carbohydrate-deficient transferrin present.Liver histology showing macrovesicular steatosis, infiltration by neutrophils, perivenular distribution of inflammation and fibrosis, Mallory bodies.
SLE
Affection of the skin (photosensitive rash), joints (arthralgia, arthritis), kidneys (nephritis or nephrotic syndrome), lungs (pneumonitis), nervous system (seizures, psychosis), serous membranes (pleuritis, pericarditis, peritonitis), and/or other organs.AIH is sometimes associated with a number of autoimmune extra-hepatic disorders similar to lupus.
ANA are present in both conditions, but SMA and AMA are rare in lupus; their presence suggests AIH.For SLE, the following are typical: anti-phospholipid antibodies, anti-dsDNA, and anti-Smith (Sm) antibodies.
Granulomatous hepatitis
Granulomas in the liver are associated with a number of disorders. Infectious disorders are the most important: bacterial (e.g., TB and other mycobacterial infections, brucellosis, tularaemia, actinomycosis); fungal (e.g., histoplasmosis, cryptococcosis, blastomycosis); parasitic (e.g., schistosomiasis, toxoplasmosis, visceral larva migrans); less common viral infections (e.g., infectious mononucleosis, CMV); and numerous others (e.g., Q fever, syphilis, cat-scratch fever).Sarcoidosis is the most important non-infectious cause; liver involvement occurs in about two thirds of patients and occasionally is the dominant clinical manifestation. Hepatic granulomas can also occur in polymyalgia rheumatica and other collagen-vascular diseases, in Hodgkin's disease, and some other systemic conditions.
Conspicuous and frequent granulomas.
Graft-versus-host disease (GVHD)
The skin, liver, GI tract, and the haematopoietic system are the principal target organs in patients with acute GVHD. Hepatic involvement is manifested by abnormal LFTs, with the earliest and most common finding being a rise in the serum levels of conjugated bilirubin and alk phos.Although the concurrent presence of the characteristic rash provides suggestive clinical evidence, biopsy is the most definitive method to diagnose GVHD of the liver.
LFTs consistent with cholestasis, with elevations in the serum alk phos and bilirubin concentrations.Histology: lymphocytic and granulomatous infiltrates of bile ducts; ductopenia.
Cryptogenic chronic hepatitis or cirrhosis
Similar clinical features.
Auto-antibodies absent.

B-Cell ALL

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Babesiosis

Malaria
Signs and symptoms may be similar. However, geographic distribution of malaria and babesiosis is different, and cyclic nature of malaria fever is absent in babesiosis.If a patient has travelled to or resides in coastal areas of the northeastern US or the lakes region of the midwest, babesiosis is more likely. If the patient has travelled to sub-Saharan Africa or tropical regions, malaria is more likely.
Giemsa- or Wright-stained thin blood smear: both Babesia microti and Plasmodium falciparum form multiple intra-erythrocytic rings, but P falciparum forms extra-erythrocytic gametocytes, whereas B microti does not. B microti may also form tetrads (Maltese cross) within RBCs.
Lyme disease
Lyme disease (Borrelia burgdorferi) is transmitted through the bite of the deer tick (Ixodes scapularis), the same vector as for Babesia microti.Signs and symptoms may be similar.Early Lyme disease may manifest with a characteristic 'bull's-eye' rash (erythema migrans).Erythema migrans is not seen in babesiosis.
ELISA or immunofluorescence for Borrelia burgdorferi antibodies.Diagnosis of Lyme disease does not exclude diagnosis of babesiosis, as co-infection can occur.
Human granulocytic anaplasmosis (Ehrlichiosis)
Caused by Anaplasma phagocytophilum. Spreads through the bite of the Ixodes deer tick, the same vector as for Babesia microti and Lyme disease.May present acutely, with fever, chills, and headache, as opposed to the more gradual onset of babesiosis. However, it may also present as a mild, self-limited illness.
Giemsa-stained thin blood smear may show the intra-granulocytic inclusions characteristic of human granulocytic anaplasmosis (HGA).Acute and convalescent phase indirect fluorescent assay may reveal antibodies against A phagocytophilum.Diagnosis of HGA does not exclude diagnosis of babesiosis, as co-infection can occur.
Rocky mountain spotted fever (RMSF)
Signs and symptoms may be similar. Both are tick-borne infections, and both may cause fever, myalgias, thrombocytopenia, and anaemia.RMSF frequently presents with a maculopapular or petechial rash, whereas a rash is rare in babesiosis.
Immunofluorescence or Luminex assay demonstrate RMSF antibodies (usually confirmed on convalescent serum).
Tularaemia
Transmitted via ticks, flies, and other arthropod vectors. Causes fever and anorexia similar to babesiosis. It can also cause septicaemia and death, even in people with intact immune systems.Unlike babesiosis, it frequently causes suppurative lymphadenitis.
Francisella tularensis can be isolated by blood culture with buffered charcoal and yeast extract or media supplemented with cysteine.
Infectious mononucleosis (EBV)
Signs and symptoms may be similar, although splenomegaly is more prevalent with EBV.Symptomatic EBV infection often affects young, otherwise healthy people, whereas babesiosis is commonly symptomatic in older or immunocompromised people.
FBC may reveal an atypical leukocytosis, as opposed to leukopenia observed with babesiosis.Heterophile antibody test is positive for EBV.
CMV
Signs and symptoms may be similar.Lymphadenopathy is commonly seen in CMV and not in babesiosis.
FBC may reveal an atypical leukocytosis, whereas babesiosis may present with leukopenia.PCR of blood or body fluids for CMV DNA confirms infection.

Bacterial meningitis

Encephalitis
Abnormal cerebral function, such as altered behaviour and speech or motor disorders, particularly when associated with fever, suggests a diagnosis of encephalitis.
Cranial imaging done by CT or MRI scans.
Viral meningitis
Relevant exposure history.No differentiating symptoms and signs.
CSF pressure is usually normal.CSF WBC count may be normal or 0.01 to 0.5 x 10^9/L (10 to 500/microlitre) and has a lymphocytic differentiation.CSF glucose is normal and CSF protein slightly elevated.Bacterial culture of CSF is negative.PCR for enteroviruses and herpes viruses.
Drug-induced meningitis
No differentiating symptoms and signs.History of culprit drug use (e.g., non-steroidal anti-inflammatory drugs, trimethoprim/sulfamethoxazole, amoxicillin, ranitidine).
This is a diagnosis of exclusion. CSF typically shows a neutrophilic pleocytosis. Symptoms resolve once the offending drug is stopped.
Tuberculous meningitis
History of contact or resident in endemic area.Symptoms and signs of pulmonary and extra-neural disease.
CSF smear and culture: sensitivity of smear >50% if repeated drops of CSF sediment dried on a slide and then stained and examined at length. Culture requires large volume for maximum sensitivity.Skin testing or interferon-gamma-based blood tests for exposure to Mycobacterium tuberculosis supportive, but negative results do not exclude diagnosis of tuberculosis.
Fungal meningitis
Presentation is often insidious with onset of headache and fever over weeks or months. A rash resembling molluscum contagiosum may be present in disseminated cryptococcal disease.
Testing CSF for cryptococcal antigen has a sensitivity of almost 100% for cryptococcal meningitis.In HIV-positive patients the fungal burden is high, leading to high CSF pressures. CSF leukocyte count may be low. India ink stain or cryptococcal antigen is usually positive.HIV-negative patients have higher CSF leukocyte counts and India ink stain is positive in only half of cases.

Balanoposthitis

Eczema and dermatitis
Characterised by erythematous scaly plaques. Pruritus is often a prominent sign.
Diagnosis is clinical.
Atopic dermatitis
Characterised by erythematous scaly patches and lichenified plaques. Pruritus is a prominent finding. Additional areas of involvement include the hands, ankles/feet, and flexural areas.
Diagnosis is clinical.Biopsy usually not necessary but may be warranted in atypical cases.A high serum IgE level strengthens clinical suspicion of the presence of the atopic tendency.
Seborrhoeic dermatitis
Lesions with slight erythema, slight to moderate scaling, and often peri-follicular or frank follicular involvement.Other commonly affected areas include scalp, ears, glabella and brows, nasolabial folds, axillae, chest, back, and groin. Slight dandruff, mild scaling of the eyebrows, or scaling lesions in the axillae or on the chest may be present.Patients typically complain of the cosmetic insult rather than of itch, which may be mild.
Diagnosis is clinical (and includes noting response to treatment).Biopsy usually not necessary but may be warranted in atypical cases.
Irritant contact dermatitis
Characterised by erythematous, scaly patch or plaque corresponding to site of application of irritant.
Diagnosis is clinical based on history, examination, and trial of treatment (i.e., avoiding presumed irritant).
Allergic contact dermatitis
Symptoms are pain, burning, or itching.Signs include erythema, swelling, vesiculation and exudation, or erythematous scaling and lichenification, depending on severity. These appear about 1 week after first contact with allergen, if previously unsensitised, or within hours to 1 to 2 days if sensitised.This is a relatively uncommon cause of balanoposthitis.
Management relies on the identification of the potential allergen and likely source, and then avoidance. There may be clues to the inciting factors at presentation, but subsequent patch testing to identify allergen(s) is required. [35]
Psoriasis
Genital psoriasis presents with variably itchy, silvery-scaled erythematous patches or plaques in circumcised men. Scale is absent from lesions on the glans penis or in the preputial sac of uncircumcised men, because of the mucosal site.Identifying other areas of involvement can help with the diagnosis of psoriasis. Commonly involved areas include the scalp, ears, umbilicus, sacrum, natal cleft, and nails.Psoriatic balanoposthitis can be part of the spectrum of inverse-pattern psoriasis (with inter-triginous and flexural site disease involvement) and may be associated with inter-triginous disease of the axillae, natal cleft, gluteal folds, and groin.Bowen disease and extra-mammary Paget's disease may be misdiagnosed as psoriasis when there are single or several foci on the penile shaft and/or in the groin.
Diagnosis of psoriasis is usually clinical; sometimes a biopsy is necessary, to exclude Zoon balanitis, lichen planus, erythroplasia of Queyrat, or Kaposi's sarcoma in uncircumcised patients with solitary mucosal lesions.
Reiter's disease
Skin lesions in Reiter's disease may be similar to those of psoriasis. Patients may present with features of both psoriasis and Reiter's syndrome.Classically, Reiter's patients have thickened yellow palms and soles with a cobblestone appearance, with or without pustular lesions (keratoderma blenorrhagica); and characteristic involvement of the penis (circinate balanitis), which, when severe, can result in balanoposthitis.
Diagnosis is clinical.Test for HLA-B27 is positive in approximately 75% of patients.
Lichen sclerosus
Men with genital lichen sclerosus may be asymptomatic. Atrophic white patches (leukoderma) or plaques are most commonly seen. The lesions can also present as hyper-trophic or lilac-coloured, slightly scaly lichenoid patches or plaques with telangiectasia and sparse purpura.Patients may report symptoms signifying sexual dysfunction or dyspareunia (itching, burning, pain, bleeding, tearing, splitting, haemorrhagic blisters), discomfort with urination, and narrowing of the urinary stream and/or concerns about the changing anatomy of their genitalia. [15] [16] [17] [18] [19] [36]Other presentations include non-retractile foreskin, paraphimosis, and urinary retention (even renal failure). The signs may be subtle with meatal narrowing and slight tightening of the prepuce (with retraction still possible) due to sclerotic plaques and bands.Severe changes due to the lichen sclerosus and associated non-specific or Zoonoid balanoposthitis include constrictive posthitis, adhesions, loss of anatomical definition, and dissolution or effacement of the normally sharply defined architectural features (e.g., frenulum and the coronal sulcus). Overt changes of Zoon balanitis may be more florid than the underlying lichen sclerosus.Other urological complications include balanoposthitis, phimosis, paraphimosis, posthitis, balanitis xerotica, and cancer.Post-inflammatory hyper-pigmentation is occasionally seen.
Most cases of lichen sclerosus can be diagnosed clinically.If there is clinical doubt, a biopsy should be done. A biopsy is mandatory if a lesion or part of a lesion is eroded or verrucous (warty).
Zoon balanitis
Well-demarcated, glistening, moist, shiny, bright-red or brown patches involving the glans and mucosal prepuce. The urethra (fossa navicularis) may also be involved. The lesions may demonstrate dark red stippling (cayenne pepper spots) and purpura with haemosiderin deposition.Atypical or unusual morphology should be viewed with suspicion and biopsied.
Screening for STDs is usually mandatory in patients with penile lesions presumed to represent Zoon balanitis.A properly targeted biopsy is advised; the pathologist should be encouraged to look for concomitant disease (e.g., lichen sclerosus), especially in the foreskin specimen following circumcision.
Non-specific balanoposthitis
Non-specific balanoposthitis is a diagnosis of exclusion and probably not common.Candidosis may be present as a secondary opportunistic phenomenon rather than as a primary cause of disease in most, if not all, cases.Preputial dysfunction is the probable cause in all cases, and in many cases lichen sclerosus will eventually be found as the underlying morbid state.
Diagnosis of exclusion.
Gonorrhoea
Erythematous patches may be well demarcated and look very similar to Zoon balanitis.Meatal, preputial, and penile oedema and, less commonly, painful lymphadenopathy may be present.
Gonorrhoea is caused by Neisseria gonorrhoeae. It is a gram-negative, intra-cellular diplococcic organism, diagnosed by a stained smear of urethral swab. Its presence is confirmed by culture or nucleic acid amplification tests.
Candidosis
Burning and soreness are more likely than itch. The glans may be eroded. Coalescent red patches or plaques involve the folds, often with superficial erosions.
Diagnosis is clinical and supported by direct demonstration of the budding forms of the yeast and pseudohyphae in a KOH preparation with India ink. Microbiological culture is confirmatory.If candidosis is diagnosed, a clinical search for an underlying dermatological or medical cause should follow, as signs due to Candida may be more obvious than those of the underlying cause.

Barrett's oesophagus

Oesophagitis
None.
Upper GI endoscopy with biopsy will show no Barrett's oesophagus findings on biopsy.
GORD
None.
Upper GI endoscopy with biopsy will show no Barrett's oesophagus findings on biopsy.
Oesophageal adenocarcinoma
May have none, or may have constitutional signs such as involuntary weight loss, low energy, and lymphadenopathy.
Biopsy reveals adenocarcinoma.
Gastritis
Patient may have a hx of chronic NSAID use.Mild epigastric tenderness common.
Upper GI endoscopy with biopsy will show no Barrett's oesophagus findings on biopsy.

Bartholin's cyst

Mucous cyst of the vestibule
Tend to be soft, <2 cm in diameter, superficial, and smooth. [13]
Diagnosis is clinical.
Vulval haematoma
Usually follows trauma or intra-operative bleeding. Extravasated blood may expand in the loose areolar tissue of the labia and cause considerable swelling. This tense swelling is exquisitely painful. [16] [18]
Diagnosis is clinical.
Vulval fibroma
Firm, not cystic, asymptomatic lesion typically occurring on the labia majora, perineal body, or introitus. [13] [16]
Diagnosis is clinical.
Vulval lipoma
Skin-coloured, soft, fatty tumour of the subcutaneous tissue; typically asymptomatic and slow-growing. [10] [18] View imageUsually in the labia majora, and further lipomas may be found on the lower abdomen or thighs. [10] [13]
Diagnosis is clinical.
Cyst of the canal of Nuck
Cystic swelling in the inguinal crease or anterior labia majora. Not crossed by the labium minus.Arises from remnants of peritoneum as it passes through the inguinal canal, so cysts may occur anywhere along the path of the inguinal canal or within the labia majora.
Diagnosis is clinical.
Epidermal inclusion cyst (sebaceous, keratinous, or epidermoid cyst)
Tend to be asymptomatic, small, and multiple, grouped together on the labia majora. [13]May have a yellowish appearance and feel firm and knobbly. [18]
Diagnosis is clinical.
Malignant lesion of Bartholin's gland
Tends to present in older women (>50 years) as an irregular nodular vulval mass, with or without ulcerations. [3] [9] View image
Biopsy of the lesion confirms or excludes malignancy.

Bartonella infection

Bacterial adenitis
Painful swollen lymph nodes with local evidence of skin involvement.
Gram stain and culture of bacteria from lesionGram stain: positiveCulture: Staphylococcus aureus or group A Streptococcus (S pyogenes).
Infectious mononucleosis
Fever, cervical lymphadenopathy, pharyngitis, rash, periorbital oedema, hepatosplenomegaly.
FBC: lymphocytosis, atypical lymphocytosis.Heterophile antibodies: positive.Epstein-Barr virus serology: positive for EBV-specific antibodies (VCA-IgM, VCA-IgG, EA, EBNA).Real-time PCR: EBV DNA detection.
Cytomegalovirus infection
Fever, lymphadenopathy, hepatomegaly.
CMV PCR or serum antigen test: positive.
Toxoplasmosis
Painless, firm lymphadenopathy, generally confined to one chain of nodes, most commonly cervical.Other manifestations include low-grade fever, hepatosplenomegaly, and rash.
Toxoplasma serology (IgM, IgG antibodies): positive.PCR: positive.
HIV infection
Generalised lymphadenopathy and low-grade fever may occur as a result of uncontrolled viraemia.
HIV serology by ELISA: positive.Western Blot assay: positive.Serum HIV rapid test: positive.
Hodgkin's disease
Typically bimodal presentation, peaking in young adults (15-35 years) and adults >55 years.Most cases (80%) have involvement of cervical and above the diaphragm lymph nodes.Some present with 'B symptoms' such as weight loss, night sweats, and fever.
Biopsy of lymph node confirms pathological features.
Tuberculosis lymphadenopathy
Associated with prolonged duration of fever, night sweats, weight loss; usually accompanied by lung findings.
Lymph node aspirate and sputum culture: positive for acid-fast bacilli.Chest x-ray: middle and lower lung zone infiltrates.Tuberculin skin test (TST): positive (millimetres of induration).Interferon-gamma release assays (IGRA): positive.
Atypical mycobacterial lymphadenopathy
Isolated or multiple cervical lymphadenopathy, associated with prolonged duration of fever, night sweats, weight loss.
Excision biopsy and culture: positive for acid-fast bacilli.
Adenoviral syndrome
Fever with conjunctivitis and lymphadenopathy, in any age group.
Adenoviral serology: a 4-fold rise in acute titres to convalescent titres is diagnostic.PCR: positive.
Tularaemia
Typically presents with abrupt onset of fever, with chills and rigors .History of travel to endemic area or recent hunting with exposure to rabbits, hares, and muskrats.
Culture of blood or other tissue samples: positive growth.Microscopy: organisms identified with bipolar staining on Giemsa's stain.Direct fluorescent antibody (DFA) test for Francisella tularensis: positive.Serology: 4-fold rise or a single titre of >1:128 by micro-agglutination assay. [25]
Salmonella infection
Prolonged febrile illness usually accompanied by high-grade fever, chills, rash, and gastrointestinal symptoms.
Blood culture: positive
Blastomycosis
History of travel to endemic area; fever and lymphadenopathy with skin lesions and/or respiratory symptoms.
Chest x-ray: lung infiltrates with hilar adenopathySputum smear and culture: large, oval, broad-based budding yeastSerology: positive
Brucellosis
Fever, history of exposure to cattle, lymphadenopathy.
Biopsy: positive for Brucella organisms.Serology test (serum agglutination test): detects antibodies against B abortus, B suis, B melitensis, and B canis.PCR: positive.
Lyme disease
History of tick exposure, erythema migrans skin lesion.
Lyme-specific IgM and IgG: positive.Skin biopsy culture: positive culture is likely from biopsy specimens from erythema migrans lesions, but is less likely in serum and CSF samples.PCR: positive results in later stages of infection.

Basal cell carcinoma

Microcystic adnexal carcinoma
Also known as sclerosing sweat duct carcinoma, this is a low-grade malignancy derived from sweat (eccrine) ducts, with high recurrence and increased incidence of metastasis. It is well known to simulate morpheaform variants of BCC, and careful histopathological examination with immunohistochemical work-up might be necessary to distinguish between the two. This type of carcinoma has a higher recurrence rate than BCC and more often necessitates Mohs surgery.
Histopathology: there are more ductal structures seen, lined by cuticle of keratin, which are not prevalent in BCCs. It will occasionally be positive with cytokeratin 7 and carcinoembryonic antigen (CEA), which are usually negative in BCCs. [31]
Trichoepithelioma/trichoblastoma
Both of these are benign neoplasms of follicular epithelium, with formation of so-called papillary-mesenchymal bodies, follicular units that simulate bulb of the hair follicle. Other distinguishing features are a lower apoptotic and mitotic rate than seen in basal cell carcinoma, and characteristic stroma-stroma split. [32] [33]
Histopathology: the characteristic stroma-epithelium split and increase in apoptotic bodies and mitotic figures is not seen. However, it is not always possible to differentiate these two, especially in the setting of prominent solar damage, and in some cases re-excision will be needed.
Merkel cell carcinoma
On the low power/lower magnification, some variants of BCC can simulate this highly malignant neoplasm derived from cutaneous neuroendocrine cells. [15]
Histopathology: Merkel cell carcinoma presents with opaque nuclei, no nucleoli, and increased nuclear/cytoplasmic ratio. Peripheral palisading might be present.Immunohistochemical work-up with cytokeratin 20, positive in Merkel cell carcinoma with a characteristic perinuclear dot-like pattern, and high molecular weight cytokeratin cocktail should distinguish it from BCC.
Squamous cell carcinoma (SCC)
Sometimes, especially on the superficial biopsy, it is impossible to distinguish BCC (either a metatypical variant of BCC or extensively rubbed BCC) and SCC. In those cases, a practitioner should not be surprised if a report suggesting both is received. In those cases, additional sampling, either in a form or larger excisional biopsy or perhaps complete excision, yields an answer. [2] [15]
Histopathology: SCC will, at least in some part of the neoplasm, reveal larger cells, with prominent nucleoli, as well as foci of keratinisation and formation of squamous whorls, where the neoplastic cells tightly wrap around each other.

Bed bugs

Insect or spider bite
Other arthropod assaults may be difficult to differentiate and are the primary consideration in the differential diagnosis.Fleas: usually lower legs.Mosquitoes: patient is aware of bite.
Clinical diagnosis.
Urticaria
Patients may have a hx of previous urticaria and/or recent exposure to trigger factor (e.g., drug or food).Lesions of urticaria due to other causes tend to be more blanchable and of shorter duration than urticarial bed bug bites
Clinical diagnosis.
Scabies
Hx of exposure to another individual with scabies.Presents as eczematous papules and patches; some lesions may become nodular; keratotic thickening can be seen on the hands.Sites of predilection are the interdigital spaces, umbilicus, groin, and axillae.Burrows (intact tunnel with a tiny dark dot, the mite, at the end) may be seen in the interdigital web spaces.
Skin scraping may reveal scabies mites, eggs, and scybala (faeces) on microscopic examination. [5]
Dermatitis herpetiformis
Hx of coeliac disease (90% of patients).A recurrent, extremely pruritic condition; typically presents with grouped (herpetiform) erythematous papules, vesicles, and excoriations distributed symmetrically on the chest, elbows, knees, lower back, and buttocks
Skin biopsy for direct immunofluorescence shows IgA in the upper dermis arranged in a granular pattern. [20]

Behcet's syndrome

Aphthous stomatitis (recurrent)
Only oral ulcers, none of the other manifestations.
None.
Crohn's disease
Genital ulcers and eye involvement less common.Rectal or anal pathology more common.
Colonoscopy and biopsy show Crohn's disease findings.
Ulcerative colitis
Genital ulcers and eye involvement less common.Rectal or anal pathology more common.
Colonoscopy and biopsy consistent with ulcerative colitis.
Herpes simplex infection
Oral ulcers may be on the outer part of the lips, not just the mucosal surface.
Cultures and serology for herpes are positive.
Necrotising vasculitis
Renal and lung vasculitic involvement possible, unlike Behcet's syndrome.
Positive anti-neutrophil cytoplasmic antibodies possible.
Seronegative spondyloarthropathies
Psoriasis, sacroiliac involvement, and penile lesions possible.
HLA-B27 associated.
Acne vulgaris
Distribution of lesions less facial and more truncal and on limbs.
None.
Erythema nodosum
Nodular lesions on limbs, self-resolving, may be painful. No oral or genital ulcers.
None. Behcet's syndrome is a cause of erythema nodosum.
Superficial thrombophlebitis
No oral or genital ulcers.
Duplex ultrasound reveals non-compressible vessel.
Rheumatoid arthritis
Mucocutaneous ulcers should be absent.
RF-positive.

Bell's palsy

Tumour
There may be progressive facial paralysis, a parotid mass, local pain, primary cancer elsewhere in the body, tinnitus, or ipsilateral eighth nerve-type hearing loss.
MRI may demonstrate benign or malignant mass lesion along the facial nerve, or in the internal auditory canal and/or cerebellopontine angle (acoustic neuroma/meningioma), parotid, or temporal bone.
Facial nerve injury
There is a hx of trauma or surgery (e.g., parotidectomy).
High-resolution CT of the temporal bone detects temporal bone fracture or facial nerve lesion.
Lyme disease
There may be fever, headache, fatigue, arthritis, skin rash (erythema migrans), hx of tick bites or exposure, or location in an endemic area.
ELISA or indirect fluorescent antibody titres to Borrelia burgdorferi are elevated.Confirmation is by Western blot assay.
Middle ear disease and complications
There may be fever, pain, ear discharge, or underlying immune compromise.
Otoscopy is abnormal in acute or chronic otitis media. High-resolution CT of the temporal bone may detect evidence of mastoiditis, petrositis, or basilar skull osteomyelitis.
Herpes zoster oticus (Ramsay Hunt syndrome)
Blisters are present on the auricular concha of the pinna.
Wound scrapings may yield multinucleated giant cells, known as Tzanck cells.Serology may be helpful (enzyme immunoassay in acute and convalescent serum) to confirm rising varicella zoster virus titres.
Rosenthal-Melkersson syndrome
There are recurrently swollen lips or face and fissured/geographic tongue.
There are no differentiating tests.
Heerfordt's syndrome
Fever, anterior uveitis, and parotid gland enlargement are present.
CXR suggests sarcoidosis. Ophthalmological examination confirms uveitis. There may be non-caseating granulomas in the parotid.
Stroke
There are signs and symptoms of other neurological dysfunction.Forehead movement is spared.
MRI or head CT scan shows evidence of stroke.

Benign paroxysmal positional vertigo

Meniere's disease
There is associated hearing loss, tinnitus, and aural fullness that is often exacerbated during an episode of vertigo.Recurrent episodes of vertigo last for minutes to hours and are not provoked by positional changes. [1] [35]
Audiogram will demonstrate a sensorineural hearing loss, usually unilateral and initially worse in the low frequencies.
Vestibular neuronitis
Often a single episode of persistent vertigo lasting for days. The vertigo can be exacerbated by any positional change, unlike the specific head movements that induce BPPV attacks.May be preceded by a non-specific viral infection. [1] [35]
Little or no nystagmus or vertigo during Dix-Hallpike testing.
Labyrinthitis
Often a single episode of persistent vertigo lasting for days. The vertigo can be exacerbated by any positional change, unlike the specific head movements that induce BPPV attacks.May be preceded by a non-specific viral infection. Hearing loss is present in viral labyrinthitis. [1] [35]
Little or no nystagmus or vertigo during Dix-Hallpike testing.Audiogram testing will demonstrate sensorineural hearing loss in cases of labyrinthitis.
Perilymphatic fistula
Is accompanied by hearing loss, tinnitus, and aural fullness.
A positive fistula test (vertigo, with or without nystagmus, induced by change in ear canal pressure) can aid diagnosis of perilymphatic fistula.
Central disorders (e.g., migraines, multiple sclerosis, posterior fossa tumours, ischaemic processes)
BPPV is a peripheral form of vertigo and should not present with or be diagnosed in the presence of neurological symptoms suggestive of a central disorder. Headaches, visual symptoms (double vision, visual field defects, visual loss), other sensory abnormalities such as paraesthesias or deficits, and motor abnormalities all suggest a central aetiology.Vertigo not precipitated by specific head movements.Central disorders can mimic BPPV attacks; however, symptoms tend to have a more gradual onset and to be less severe and less transient. [1] [35]
During Dix-Hallpike testing for posterior canal BPPV, the nystagmus may not fade away or fatigue, lacks a torsional (rotatory) component, and can be purely vertical. [1] [35]CT and/or MRI scans of the head can aid diagnosis of many central disorders that may mimic BPPV.

Benign prostatic hyperplasia

Overactive bladder
Frequent urge to urinate with possible incontinence and nocturia.
Bladder ultrasound with low post-void residuals.Abnormal pressure flow studies.
Prostatitis
Fever, suprapubic or low back pain, tender, enlarged prostate gland on rectal examination is more consistent with prostatitis.
Elevation of white count.Abnormal urinary sediment.Possible elevation of PSA.
Prostate cancer
Abnormal digital rectal examination with prostate nodules or asymmetry is more consistent with prostate cancer.
Elevated PSA for age.Low free PSA.Increased PSA velocity greater than 0.75 nanograms/mL/year.
UTI
Presence of fever, dysuria, suprapubic or low back pain is more consistent with UTI.
Abnormal urinalysis with pyuria and positive urinary culture.
Bladder cancer
Haematuria, suprapubic pain, bladder spasms with abnormal voiding, history of tobacco abuse, unknown major risk factor is more consistent with bladder cancer.
Microscopic haematuria on urinalysis.Abnormal findings on cystoscopy.Abnormal bladder mass effect with invasion on imaging studies such as ultrasound and CT.
Neurogenic bladder
Storage abnormality in patients with involuntary bladder contractions.Usually seen in patients with vascular disease, Parkinson disease, multiple sclerosis or diabetes mellitus with neuropathy. [15]
Abnormal urodynamic studies with increased residual volume or catheterisation following voiding or on ultrasound.
Urethral stricture
History of straddle injury or prior urological surgery with obstructive symptoms is more consistent with urethral stricture.
Abnormal retrograde urethrogram, cystoscopy, diminished peak flow on uroflowmetry.

Benign tongue lesions

Melkersson-Rosenthal's syndrome (fissured tongue)
Triad of presence of significant lip enlargement (granulomatous cheilitis) and intermittent seventh (facial) nerve palsy in association with the fissured tongue. However, the triad of symptoms do not all have to be present at a given time.
Tongue biopsy may exhibit presence of non-caseating granulomas.
Oral hairy leukoplakia (hairy tongue)
Painless white plaques along the lateral tongue borders. History of HIV or immunosuppression. [8]
Tongue biopsy with immunostaining of the specimen for Epstein-Barr virus (EBV), the causative agent for oral hairy leukoplakia.
Mucosal candidiasis (hairy/geographic tongue)
White patches resemble milk curds and when wiped off reveal a raw erythematous and sometimes bleeding base.
Cytology with potassium hydroxide preparation for diagnosis of candidal organisms.
Contact stomatitis (geographic tongue)
The presence of perioral and lip dermatitis may aid in making the diagnosis. Also the patient may report an inciting factor such as mouthwashes, toothpastes, dental materials, and gum.
Patch testing for contact allergen. RAST (radioallergosorbent test) for specific immunoglobulin E (IgE) for food and latex allergy.

Benzodiazepine overdose

Alcohol or other sedative or hypnotic drug overdose
History of alternative drug or alcohol intake, bottles of pills, signs of drug use such as needle marks, smell of alcohol.
Elevated serum ethanol or other drug levels.
Hypoglycaemia
History of diabetes; patient may be pale and sweaty.
Serum glucose <2.8 mmol/L (<50 mg/dL).
Hyponatraemia
Severe metabolic abnormalities such as hyponatraemia can be a cause of coma but would not normally be confused with benzodiazepine (BZD) overdose because there is usually a history of preceding illness.
Serum sodium <135 mmol/L (<135 mEq/L).
Hyperosmolar coma
Severe metabolic abnormalities such as hyperosmolar coma can be a cause of coma but would not normally be confused with BZD overdose because there is usually a history of preceding illness such as diabetes.
Serum osmolality >320 mmol/kg (>340 mOsm/kg).Serum glucose >33.3 mmol/L (>600 mg/dL).
Stroke
There should be no difficulty distinguishing focal neurological causes of coma such as stroke, as there should be a history of rapidly developing neurological deficit plus focal neurological signs on examination.
Brain CT or MRI shows area of ischaemia or infarction.
Meningitis
The diagnosis of meningitis is normally suggested by a typical history of fever, headache, and neck stiffness, and should not be confused with BZD overdose except in the case of an undifferentiated coma.
CSF abnormalities such as elevated protein usually present.Brain MRI or CT scan may reveal complications such as cerebral oedema.
Encephalitis
Serious, complex, and potentially fatal disorder with non-infectious and infectious causes. Patients usually present with acute onset of a febrile illness and altered mental status; typical features include headache, seizures, and focal neurological signs. Encephalitis should not be confused with BZD overdose except in the case of an undifferentiated coma.
Findings on CSF analysis and brain MRI often reflect the underlying aetiology.
Post-ictal state
Psycho-motor retardation or other CNS depression following seizure may be confused with BZD overdose, although history of seizure disorder is usually present.
EEG may show signs of recent seizure but diagnosis is usually clinical.

Beta-thalassaemia

Congenital dyserythropoietic anaemia (CDA)
There may be no differences in signs and symptoms, but it is likely there will be no family history of thalassaemia, and the child may not be of an ethnic background noted for beta-thalassaemia (Mediterranean, Southeast Asian, Middle Eastern).
Anaemia in CDA is usually macrocytic, as opposed to the microcytic anaemia found in classical beta-thalassaemia syndromes. Haemoglobin electrophoresis in CDA may show an elevated HgbF, but most of the haemoglobin is HgbA, whereas in beta-thalassaemia major or intermedia there is minimal or no HgbA.
Pyruvate kinase (PK) deficiency
Usually presents in the neonatal period with prolonged and severe hyperbilirubinaemia. Anaemia is profound, and hepatosplenomegaly and skeletal changes may develop in infancy. Moderate icterus is almost always present.
Anaemia in PK deficiency is usually not microcytic as in thalassaemia. The peripheral smear is remarkable for the very large number of nucleated red cells; fewer such cells are seen in beta-thalassaemia. Haemoglobin electrophoresis in PK deficiency shows a preponderance of HgbA, whereas in beta-thalassaemia major or intermedia there is minimal to no HgbA.
Mild iron deficiency anaemia
The clinical presentation of beta-thalassaemia trait is similar to that of mild iron deficiency anaemia. Symptoms of anaemia may be mild or absent in both. In iron deficiency anaemia, there may be a history/finding of blood loss (overt or occult, usually chronic) and/or a history of a diet poor in iron-rich foods. Otherwise the diagnosis must be made based on laboratory tests.
In beta-thalassaemia trait, fasting serum iron and transferrin saturation are usually normal, whereas both are low in iron deficiency states. There is a mild microcytic anaemia in both, but the red cell distribution width (RDW) is usually elevated only in iron deficiency. [12] The Mentzer index has also been used to distinguish the two conditions. [13] An index >13 is highly suggestive of iron deficiency anaemia.Haemoglobin electrophoresis will confirm the diagnosis of beta-thalassaemia trait.
Alpha-gene mutations (alpha-thalassaemia major, haemoglobin H disease, haemoglobin Constant Spring)
Alpha-thalassaemia major generally presents as hydrops fetalis at birth or may be diagnosed in the intrauterine period on routine ultrasound. These patients/families usually have Chinese ancestry.Haemoglobin H disease may have the same clinical presentation as beta-thalassaemia intermedia, with chronic moderate to severe microcytic anaemia, elevated bilirubin levels, propensity for developing gallstones.Haemoglobin Constant Spring has the same phenotype as alpha-thalassaemia major.
The clinical presentation of alpha-thalassaemia major and haemoglobin Constant Spring are quite different from that of beta-thalassaemia. Haemoglobin H disease may be distinguished based on the haemoglobin electrophoresis, which will show some haemoglobin A and a specific band of haemoglobin H (tetramer of 4 beta-globin chains).
Haemolytic anaemia
Presents with acute or subacute development of fatigue or jaundice, and may include orthostasis and mild splenomegaly. Common causes include autoantibodies, medications, and underlying malignancy. If the course is insidious and the anaemia is longstanding, beta-thalassaemia trait or intermedia may be considered in patients of the appropriate ethnicity.
FBC will show normocytic anaemia with elevated MCHC, whereas in beta-thalassaemia, the anaemia is microcytic and the MCHC is low. Direct antiglobulin test (Coombs) is important for differentiating immune from non-immune aetiologies of haemolysis. Peripheral smear review is important in identifying underlying cause.
Anaemia of chronic disease
History of acute and chronic infections, autoimmune disorders, major trauma and surgery, and critical illness, with physical examination findings of the underlying disorder. May consider beta-thalassaemia trait in such situations.
The degree of anaemia is typically mild to moderate (Hb 80 to 110 g/L (8 to 11 g/dL)) and normocytic. WBC and differential and platelet count may be elevated due to associated infection or inflammation. In beta-thalassaemia trait, the anaemia is microcytic and the haemoglobin electrophoresis is abnormal with elevated haemoglobin A2 and often haemoglobin F as well.

Biliary atresia

Extrahepatic biliary obstruction (e.g., choledochal cyst, spontaneous perforation of common bile duct, bile duct stricture or tumour, neonatal sclerosing cholangitis)
Tumour or mass may be felt on palpation.Spontaneous perforation can present with ascites or jaundice around the umbilicus associated with a tender abdomen.Biliary strictures may form following liver transplantation.
Ultrasound: may demonstrate tumour, bile duct dilation before a stricture, or a choledochal cyst.ERCP will demonstrate bile duct stenosis.Cholangiogram needed to differentiate from neonatal sclerosing cholangitis.
Hepatic viral infections (e.g., CMV, enterovirus, HSV, echovirus, adenovirus, hepatitis B virus, HIV, rubella, reovirus type 3, parvovirus B19, EBV)
Infant may be septic or have petechiae and rashes.Intracranial calcifications may be seen on cranial x-ray (periventricular calcifications).
Viral serology.Urine for CMV antigens, urine culture.Viral swabs from nasal passages or rectum for enteroviruses.
Alagille's syndrome
Bile duct paucity, butterfly vertebrae, posterior embryotoxin (congenital eye abnormality), characteristic facies, cardiac/renal anomalies.
Liver biopsy: a paucity of bile ducts.CXR: butterfly shape of vertebrae.Echocardiogram: cardiac anomaly.Facies: broad forehead, pointed chin.Genetic testing for the JAG1 gene.
Alpha-1 antitrypsin deficiency
FHx of lung disease at an early age.
Genetic screening: protease inhibitor typing (blood test to look for protease inhibitor by gel electrophoresis).
Down's syndrome
Hypotonia, characteristic dysmorphic features.
Karyotype: trisomy 21.
Turner's syndrome
Neonatal pedal oedema, lymphoedema.Webbed neck.
Karyotype: 45 X cell line or a cell line with deletion of the short arm of the X chromosome (Xp deletion).
Progressive familial intrahepatic cholestasis
Clinical presentation indistinguishable but typically presents at about 3 months of age. May be FHx.
Liver biopsy: no inflammation, few bile ducts, giant cells may be seen, biliary epithelium apoptosis.Genetic testing can be performed for research purposes.
Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease
Renal insufficiency, hepatomegaly with predominant involvement of the left lobe.Aminotransferase enzymes usually normal.
Ultrasonography reveals evidence of intense hepatic echogenicity and evidence of portal hypertension.Enlargement and polycystic changes of kidneys with increased echogenicity.
Caroli's disease
Fever if cholangitis is present, abdominal pain, nausea and vomiting, mass if large polycystic kidneys.
Ultrasonography: cystic lesions and intrahepatic bile duct dilation.Magnetic resonance cholangiography: irregular dilation of the large intrahepatic bile ducts.
North American Indian childhood cirrhosis
Severe non-syndromic cholestasis only described in North American Indian children. May present with bleeding varices.
Genetic testing: missense mutation of the cirhin gene, found on chromosome 16q22.
Rotor's syndrome
May have episodes of fever, intermittent abdominal pain described, chronic jaundice, not itchy.
Elevated conjugated and non-conjugated bilirubin with normal transaminases and excretion of tracer during hepatobiliary scintigraphy.Urine coproporphyrin ratios and normal liver histology.
Dubin-Johnson syndrome
Presentation with jaundice.Tends to present later in childhood.
Elevated bilirubin but with normal transaminases.Increased ratio of urinary coproporphyrin I to coproporphyrin III.Intense and prolonged visualisation of the liver with delayed or absent visualisation of the gallbladder on hepatobiliary scintigraphy scan.
Cystic fibrosis
Failure to thrive, excessive mucus production, lung infections, fatty diarrhoea, meconium ileus.
Elevated sweat chloride, cystic fibrosis transmembrane conductance receptor gene mutations.
Neonatal iron storage disease
Oedema, jaundice, splenomegaly.May be premature or have oligohydramnios during pregnancy.
Positive iron staining of buccal biopsy.MRI may show extrahepatic siderosis (pancreas, myocardium).
Hypothyroidism
Poor feeding, constipation, hypothermia.
Thyroid function tests: low levels of T4 with high levels of TSH.Predominantly unconjugated hyperbilirubinaemia.
Panhypopituitarism
Midline malformations, nystagmus, hypoglycaemia.
Hormonal tests show reduced levels of pituitary hormones.Neurological imaging: abnormality of pituitary gland (appearance will depend on cause for reduced pituitary function).
Galactosaemia
Vomiting and failure to thrive, congenital cataracts, may have associated Escherichia coli sepsis.
Positive urine reducing substances. Reduced RBC galactose-1-phosphate uridyl transferase activity.
Hereditary tyrosinaemia
Failure to thrive, coagulopathy, distinctive cabbage-like odour.
Elevated succinylacetone in blood or urine.
Niemann-Pick disease
Hepatosplenomegaly usually without liver dysfunction, failure to thrive, hypotonia.
Cherry-red spot on ophthalmological examination.Decreased acid sphingomyelinase activity in peripheral blood WBCs or cultured fibroblasts.
Wolman's disease
Severe hepatomegaly, failure to thrive, vomiting, diarrhoea, splenomegaly, and ultimately liver failure.
Liver biopsy: fatty infiltration.Lysosomal acid lipase deficiency.
Hereditary fructose intolerance
Onset of symptoms coincides with introduction of fructose-containing formula or foods.
Molecular analysis of aldolase B gene.
Glycogen storage disease IV
Can present in infancy with hepatosplenomegaly, cirrhosis, and liver dysfunction.
Liver biopsy: excessive abnormal glycogen storage.Muscle biopsy: branching enzyme deficiency detected by polyglucosan inclusions.
Mitochondrial disorders
Neonatal liver failure, lactic acidosis, seizures.
Elevated blood lactate-pyruvate ratio.Electron microscopy of liver biopsy: evidence of mitochondrial disorder.Genetic testing for specific defects.
Peroxisomal disorders (e.g., Zellweger's, infantile Refsum disease, mevalonate kinase deficiency)
Craniofacial and neurological abnormalities in association with jaundice.
Best initial test is plasma very long-chain fatty acid analysis by gas chromatography.
Bile acid synthesis defects
Hepatosplenomegaly.
Normal gamma-GT, elevated transaminases.Urinary bile acid analysis by fast atom bombardment ionisation mass spectrometry.
Toxic causes: drugs, total parenteral nutrition, endotoxin from gram-negative bacteria
Onset of jaundice related to timing of exposure to toxin.May be systemically unwell with fever and rash.
No specific test. Relies on temporal relationship and treatment of suspected cause (e.g., sepsis, cessation of total parenteral nutrition or drug, and resolution of symptoms) to confirm diagnosis.
Sepsis
Onset of jaundice related to timing of exposure to toxin.May be systemically unwell with fever and rash.
No specific test. Relies on temporal relationship and treatment of suspected sepsis to confirm diagnosis.
Idiopathic neonatal hepatitis
Clinically indistinguishable.
Liver biopsy shows giant cell transformation.
Ischaemia-reperfusion injury
Typically occurs after an infant has been profoundly ill.
Liver biopsy shows centrilobular injury with periportal preservation.
Inspissated bile
Clinically indistinguishable.May be found in cystic fibrosis or after significant haemolysis.
Ultrasound of bile ducts: intrabiliary bile plugs.
Congenital heart disease
Cyanosis, low oxygen levels, low blood pressure, known cardiac defects.
Echocardiogram: will determine cardiac anomalies.

Bipolar disorder in adults

Mood disorder due to general medical condition
May be clinically indistinguishable; however, people often have atypical mood symptoms.Symptoms and signs specific for the underlying medical condition (e.g., stroke, thyroid disease, and multiple sclerosis) may be present.
Specific testing based on suspected underlying condition. May include CT head, MRI brain, and thyroid function testing.
Substance-induced mood disorder
May be clinically indistinguishable.The mood disorder is judged to be temporally associated with exposure to the causative substance. Withdrawal states from some substances can last for up to 4 weeks.
Laboratory findings, including blood alcohol level and toxicology screens.
Major depressive disorder
Criteria include depressed mood most of the day, as self-reported or observed by others; diminished interest or pleasure in all or almost all activities; significant weight loss when not dieting, weight gain, or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate; recurrent thoughts of death, recurrent suicidal ideation without a specific plan. [1]However, patients have never had a manic, hypomanic, or mixed episode.
Clinical diagnosis using DSM-IV-TR criteria for major depressive disorder.
Dysthymic disorder
A form of depression characterised by a chronic course (persistent for 2 years or longer).Symptoms of dysthymic disorder include 2 of the following: poor appetite/overeating, insomnia/hypersomnia, low energy/fatigue, low self-esteem, poor concentration, feelings of hopelessness.However, patients have never had a manic, hypomanic, or mixed episode.
Clinical diagnosis using DSM-IV-TR criteria for dysthymic disorder.
Cyclothymic disorder
Cyclothymic disorder is characterised by a minimum duration of 2 years marked by numerous periods of hypomanic symptoms that do not meet criteria for a manic episode, and numerous periods with depressive symptoms that do not meet criteria for a major depressive episode. During the 2-year period, the person has not been without mood symptoms for >2 months at a time.
Clinical diagnosis using DSM-IV-TR criteria for cyclothymic disorder.
Psychotic disorders
Psychotic disorders such as schizophrenia, schizoaffective disorder, and delusional disorder are all characterised by periods of psychotic symptoms that occur in the absence of prominent mood symptoms.
Clinical diagnosis using DSM-IV-TR criteria.
Personality disorders
A personality disorder is an enduring pattern of inner experience and behaviour that deviates from cultural expectations and is marked by persistent disturbances in cognition, affectivity, interpersonal functioning, and impulse control.The pattern is maladaptive, inflexible, pervasive, stable, and of long duration, in contrast with the episodic nature of bipolar disorder.
Clinical diagnosis using DSM-IV-TR criteria.
Obsessive-compulsive disorder
Anxiety disorder characterised by persistent or repetitive thoughts (obsessions) and/or behaviours (compulsions) experienced as unwanted, excessive, and unpleasant by the patient.The obsessions or compulsions are recognised by the person as excessive or unreasonable at some point during the course of illness, and cause marked distress, consume additional time, or significantly interfere with functioning.
Clinical diagnosis using DSM-IV-TR criteria.
ADHD
Symptoms of inattention, hyperactivity-impulsivity must be present in 2 or more settings (e.g., at work and at home) with clear evidence of clinically significant impairment in social, academic, or occupational functioning.These ADHD symptoms must not occur exclusively during the course of a manic, hypomanic, or depressive episode, or any other mental disorder.Problems with attention, hyperactivity, and/or impulsiveness noted to have emerged before age 7 years may persist into adulthood and confound the diagnosis of bipolar disorder.
Clinical diagnosis using DSM-IV-TR criteria.

Bladder cancer

Benign prostatic hyperplasia
Can cause haematuria and occurs in the same age and gender group as bladder cancer.BPH is associated with reduced force of stream, frequency, urgency, and nocturia, as well as enlargement of the prostate on digital rectal examination. However, BPH is so common that these signs and symptoms provide essentially no aid in clinical differentiation.
Urine cytology should be normal with BPH, but it is also often normal with low-grade bladder tumours.Cystoscopy with biopsy of suspicious lesions: BPH and low-grade tumours are visible; carcinoma in situ and high-grade solid tumours, which may not be visible, should have positive cytology.Imaging studies may show an inferior bladder mass.
Haemorrhagic cystitis
Acute onset of severe frequency and dysuria in a young woman, particularly if associated with low back pain and malaise, suggests haemorrhagic cystitis. However, it can be difficult to distinguish from bladder cancer by clinical features alone.
Urine culture should be positive with cystitis. Resolution of haematuria is not an indication of benign disease. Cystoscopy is indicated for haematuria in the absence of a bacterial source, even when cytology is normal.
Prostatitis
Typically occurs in men <55 years old. Prostatitis tends to be more relenting than malignant causes of dysuria and pelvic pain.
Cytology is key to the differentiating prostatitis and carcinoma of the bladder or prostate.Cystoscopy and biopsy may also be required.
Urinary tract infection
Repeated UTI is a risk factor for bladder cancer. Symptoms of urgency, frequency, dysuria, and haematuria are shared by both UTI and bladder cancer and do not aid clinical differentiation. Back pain, fever, and chills are common with UTI, but rare with bladder cancer.
Cytology and cystoscopy are key to the diagnosis of bladder cancer. Positive urine culture makes bladder cancer the less likely, but does not exclude the diagnosis.
Nephrolithiasis
A common cause of gross and microscopic haematuria, nephrolithiasis can be distinguished by typical symptoms of renal colic when present.
Non-contrast CT scan will demonstrate stones, even uric acid stones. A plain x-ray can be diagnostic for radiopaque stones.Inflammation from chronic foreign bodies and stones promotes transitional cell carcinoma (TCC); bladder and upper tract tumours may calcify, but imaging typically reveals the associated mass.
Renal cell carcinoma
Ureteral casts can cause vermiform clots to signify upper tract haemorrhage. Bladder symptoms are infrequent. Rarely a renal mass may be palpable. Flank pain is uncommon, but may occur with clot obstruction, bleeding into the mass, or infiltration of perirenal structures.
Abdominal and pelvic CT scan with and without contrast will typically reveal renal cell carcinoma. Anaemia and elevated sedimentation rate are common, and abnormal liver function tests, even in the absence of metastasis, occur not infrequently.
Renal transitional cell carcinoma
Renal pelvic and ureteral TCCs have aetiology and symptoms similar to TCC of the bladder: haematuria and, much less frequently, dysuria. Vermiform clots indicate upper tract bleeding.
CT urogram or intravenous pyelogram may show upper tract tumour. Cystoscopy, ureteroscopy, and bladder and upper tract cytology and biopsy can differentiate the site of malignancy.
Gynecological cancer or other pelvic cancers
Symptoms of pelvic pain and mass are rare with bladder cancer, and somewhat more common with other tumours. Pelvic examination may reveal cervical, uterine, or pelvic mass in women. Digital rectal examination may detect rectal carcinoma or, in men, prostatic induration suggestive of prostate cancer.
CT scan and, if needed, cystoscopy with cytology and biopsy can differentiate these cancers.
Radiation cystitis
Signs and symptoms indistinguishable from bladder cancer. Requires history of radiation exposure.
Cystoscopy shows increased vascularity with irregular, tortuous vessels and inflammation. Biopsy and cytology, sometime repeated, are required to differentiate.
Diverticulitis
Sigmoid diverticulitis can cause bladder inflammation with irritative symptoms and haematuria.Colovesical fistula occurs most commonly as complication of diverticulitis, which may cause pneumaturia, along with possible discolouration and malodour in the urine. Physical examination may show a pelvic mass.
CT scan may show diverticulitis, and is the study of choice to demonstrate fistula with air in the bladder. Bladder mass suggestive of high-stage, invasive bladder cancer can be seen on both CT and cystoscopy, making biopsy critically important before treatment for suspected bladder cancer.

Blastomycosis

Community-acquired pneumonia
Acute pulmonary blastomycosis is commonly mistaken for community-acquired pneumonia. Failure to respond to antibacterial therapy and extrapulmonary manifestations are clues to the aetiology.
Findings of blastomycosis on chest x-ray can be atypical for community-acquired pneumonia, and include mass-like or cavitary lesions or diffuse interstitial infiltrates. View imageView imageView image
Histoplasmosis
Histoplasmosis and blastomycosis share many of the same clinical manifestations, and the endemic areas overlap to a great extent.However, sputum in blastomycosis is generally purulent, in contrast to histoplasmosis.
Differentiation between these 2 diseases often relies on culture data. Histoplasma yeast are typically smaller, have narrow based budding, and are found intracellularly within macrophages in clinical specimens. There is some cross-reactivity with serological and antigen assays for these 2 organisms.
Coccidioidomycosis
Coccidioidomycosis and blastomycosis share many of the same clinical manifestations. However, the endemic area of Coccidioides is the desert region of the south-western US.
Serological testing for coccidioidomycosis is of higher sensitivity than for blastomycosis, and the yeast in pathological specimens appears as the characteristic spherule.
Paracoccidioidomycosis
Acute/sub-acute paracoccidioidomycosis more often presents with lymphadenopathy, hepatosplenomegaly, and bone marrow dysfunction, while chronic paracoccidioidomycosis generally presents with dry cough and dyspnoea.Paracoccidioidomycosis is also endemic to Central and South America.
Paracoccidioides yeast are typically smaller than Blastomyces dermatitidis with thinner cell walls, and can be found in the mariner wheel formation, with multiple small budding yeast circumferentially surrounding the parent cell. [19]
Sporotrichosis
The cutaneous lesions of sporotrichosis are similar in appearance to blastomycosis. However, lymphadenitis (generally nodular and subacute to chronic) is pathognomonic in sporotrichosis.
Microbiological and pathological examination of skin biopsies will yield the diagnosis.
Tuberculosis
Cutaneous disease is less common in tuberculosis than in blastomycosis.
Acid fast smear and mycobacterial culture of clinical specimens generally lead to the diagnosis of tuberculosis. Tuberculin skin testing and the in vitro interferon gamma release assays of sensitised lymphocytes are also helpful in diagnosis of tuberculosis.
Nocardiosis
Nocardiosis and blastomycosis share many of the same clinical features. Nocardia is more common in immunocompromised people and has a worldwide distribution.
Microbiological examination of clinical specimens in nocardiosis reveal thin, branching gram-positive bacilli that stain positively by the modified acid fast stain. Culture of Nocardia species is confirmatory of that diagnosis.
Malignancy
The pulmonary, cutaneous, osteoarticular, and CNS manifestations of blastomycosis can all be mistaken for primary or metastatic neoplasms.
Pathological examination of tissue specimens can confirm or rule out malignancy.

Blast crisis

Organ-specific or systemic infection (bacterial, fungal, viral)
Presents outside the context of immunosuppression and neutropenia.
Gram stain or cultures of body fluids or bone marrow may grow relevant organisms.Imaging studies where indicated may identify source of infection.Skin testing may indicate tuberculosis.Leukocyte alkaline phosphatase will be high in infection while it is low in chronic myelogenous leukemia (CML).Philadelphia chromosome (breakpoint chromosome region-Abelson, BCR-ABL) rearrangement are absent.
Leukemoid reaction
Underlying cause of leukemoid reaction - that is, corticosteroid use, infection, inflammatory disease, stress reaction - may be identified clinically.
Leukocyte alkaline phosphatase will be high in infection while it is low in CML.
Essential thrombocythaemia
Symptoms and signs are non-specific and may not differ from those of blast crisis.Although blast crisis usually presents with low platelets, it can occasionally present with thrombocytosis.
JAK2 mutation, if present.Bone marrow examination shows no blasts, with increased megakaryocytes.No WBC or RBC abnormalities.Philadelphia chromosome (BCR-ABL rearrangement) absent.
Atypical CML, Philadelphia chromosome-negative
Symptoms and signs are non-specific and may not differ from those of blast crisis.
Philadelphia chromosome (BCR-ABL rearrangement) absent.
Chronic myelomonocytic leukemia
Symptoms and signs are non-specific and may not differ from those of blast crisis.
Philadelphia chromosome (BCR-ABL rearrangement) absent.Monocytosis is prominent.
Philadelphia-positive acute lymphoblastic leukemia
Symptoms and signs are non-specific and may not differ from those of blast crisis.
Difficult to distinguish from blast phase of CML.BCR-ABL tyrosine kinase locus is 190 kd instead of 240 kd, and additional cytogenetic abnormalities may be present.
Philadelphia-positive acute myelogenous leukemia
Symptoms and signs are non-specific and may not differ from those of blast crisis.
Difficult to distinguish from blast phase of CML.Usually additional chromosomal abnormalities are present.

Blepharitis

Dry eye syndrome
May present with symptoms similar to those of blepharitis.Fluorescein staining in dry eye syndrome typically involves the interpalpebral zone. In blepharitis the lower third of the cornea is more commonly involved.Slit lamp findings of collarettes and capped meibomian glands are more suggestive of blepharitis.
Schirmer's test shows reduced tear production.Tear film break-up time is decreased.These tear film abnormalities are also common in blepharitis but would generally have debris and saponification of the tear film in addition.
Chalazion
Focal tenderness or nodule on eyelid caused by blocked glands.Commonly also a sign of associated underlying blepharitis.
Lid biopsy shows lipogranulomatous inflammation--histiocytes and multi-nucleated giant cells enveloping optically clear spaces.Lymphocytes, plasma cells, and neutrophils may also be present.
Squamous cell carcinoma
Unilateral lid changes, lid architecture distortion including ulceration, lash changes or loss. [26]
Lid biopsy shows atypical squamous cells forming nests and strands, infiltrating the dermis, with desmoplastic fibrous tissue reaction.
Basal cell carcinoma
Unilateral lid changes, pearly nodule with telangiectasis, lash changes or loss, lid architecture distortion.
Lid biopsy shows peripheral palisading basal cells.
Sebaceous cell carcinoma
Unilateral lid changes, recurrent or non-resolving chalazion, lid architecture distortion, lash changes or loss. [26]
Lid biopsy shows nests with central necrosis, foamy cytoplasm.

Brachial plexus injury

Functional, psychogenic, or hysterical weakness (e.g., unilateral loss of motor function or psychogenic parkinsonism)
Psychological disorders may mimic relevant clinical findings.Psychological assessment may be useful in diagnosis.Referral to a specialist may be appropriate when obvious antecedent causes of paralysis are absent.
Electrical testing is confirmatory of non-physiological causes of paralysis and sensory loss.
Amyotrophic lateral sclerosis (ALS)
Progression of muscle weakness and atrophy.Involvement of other body sites.The progression of muscle weakness or sensory loss can help differentiate ALS from other neurological disorders.
Electrical testing (EMG and/or NCV) can be used to assess for evidence of diffuse, on-going, chronic denervation in ALS.
Brain or spinal cord injury
The history and clinical examination may help to differentiate the conditions according to the site of injury.
MRI or other imaging. Imaging can reveal injury to the brain or spine.
Pancoast tumour
There may be no differences in signs and symptoms initially.Horner's syndrome and paraplegia may develop.
MRI of the apex of the lung and brachial plexus. Imaging can show the tumour and its relationship to the brachial plexus.

Bradycardia

Ventricular bigeminy
Post-premature ventricular contraction (PVC) potentiation not present during sinus rhythm without PVCs.Cannon a-waves seen in the jugular venous pulse.
ECG and rhythm strip correlated with pulse show a premature ventricular beat after each normal beat.
Frequent premature ventricular contractions (PVCs)
Non-perfused ventricular ectopy causing apparent sinus bradycardia.Patients are usually asymptomatic.Cannon a-waves may be seen in the jugular venous pulse.
ECG and rhythm strip correlated with pulse. Specific ECG findings depend on the cause. However, ventricular beats occur earlier than normal.
Atrial fibrillation
Apical versus peripheral pulse.Irregular pulse rate.
ECG shows absent P waves, presence of fibrillatory waves, and irregular QRS complexes. Rhythm strip may be useful.
Blocked premature atrial contractions (PACs)
Atrial rate is fast but ventricular rate is slow.
ECG shows slight notching on preceding T-wave.
Ventricular tachycardia
A-waves, variable S1, and variable pulse seen in jugular venous pressure.
ECG shows atrioventricular (AV) dissociation with capture and fusion.
Cardiac tamponade
Muffled heart sounds.Sinus tachycardia.Pulsus paradoxus (usually below 10 mmHg).Elevated jugular venous pressure.
ECG shows low voltage, QRS, or total electrical alternans.Echocardiogram shows large pericardial effusion or chamber collapse and respiratory variation of ventricular filling.

Brain abscess

Primary CNS neoplasm
Presentation may be identical, but less likely to include meningismus or fever.Infectious source absent.Presentation over a protracted period, with symptoms lasting several weeks to months, favours the diagnosis of neoplasm.
WBC count, ESR, and CRP are generally not elevated. [33] MRI more often demonstrates a heterogenous appearance. Magnetic resonance spectroscopy (MRS) lacks succinate, acetate, and amino acid elevations. Ultimately differentiated by surgical sampling of the lesion.
Metastatic lesion
Rarely exhibits fever and meningismus. Infectious source absent.History or signs and symptoms of the primary neoplasm may be present.
CT chest, abdomen, and pelvis, or possibly bone scan or mammogram, reveal the primary lesion in most cases. Occasionally presents as a cryptogenic lesion. Tissue diagnosis by surgical biopsy or resection is definitive.
Recurrent tumour/radiation necrosis in a post-surgical patient
Time course generally distinguishes radiation necrosis, which occurs after a full course of radiotherapy.Often asymptomatic. Fever and meningeal signs absent.
Elevated WBC count more indicative of abscess unless the patient remains on corticosteroids.MRI generally shows fluid in the surgical cavity that is consistent with a purulent collection in brain abscess.Magnetic resonance spectroscopy (MRS) lacks peaks associated with metabolic activity in radiation necrosis.If suspicion persists, surgical re-exploration is indicated.
Multiple sclerosis
Longer history of protean neurological symptoms.Fevers and meningismus absent.Occurs in characteristic population.Presence of specific signs: Lhermitte's sign (transient electric-like shocks extending down the spine), Uhthoff's sign (episodic transient obscuration of vision).
CSF analysis, if LP is performed, shows characteristics of MS.MRI demonstrates exclusively white matter lesions that fluctuate over time and vary with their degree of enhancement.
Acute disseminated encephalomyelitis (ADEM)
History of prior inflammatory event or vaccination.More common in children and patients from tropical climates.
MRI shows lesion restricted to white matter. Evoked potentials consistent with demyelination.
Ischaemic stroke
Lack of fever and meningeal signs. Presents as sudden neurological deficit that is relatively stable afterwards. Headache is rare.
Lack of elevated ESR, CRP, WBC count. MRI rarely exhibits contrast enhancement except for pseudolaminar necrosis. Diffusion-weighted images on MRI show characteristic findings depending on timing of study.Limited to a single vascular distribution.

Brain Tumor (MEDULOBLASTOMA, EPENDIMOMA)

Migraine
Family history of migraine.Aura may be present.Headache does not occur daily and is not worse in the morning.
Neuroimaging of the brain will be normal.
Viral infection
Sick contacts at home or school.Associated with fever, myalgias, arthralgias, diarrhoea, or rhinorrhoea.Vomiting not just in morning; symptoms do not improve after vomiting.
Blood work shows elevated WBC.Neuroimaging of the brain will be normal.
Ependymoma
Ataxia more common.
tumour in region of foramen of Luschka on MRI.Calcifications on brain CT. [27]Biopsy of lesion confirms diagnosis.
Juvenile pilocytic astrocytoma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Cystic with enhancing nodule. [27]Biopsy of lesion confirms diagnosis.
Fibrillary astrocytoma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Biopsy of lesion confirms diagnosis.
Ganglioglioma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Biopsy of lesion confirms diagnosis.
Atypical teratoid/rhabdoid tumour
Very difficult to distinguish from medulloblastoma. Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar vermis and growing into and filling the fourth ventricle on neuroimaging. [27]Very difficult to distinguish from medulloblastoma.Similar histology to medulloblastoma; however, immunohistochemistry will show absence of staining for the product of the tumour suppressor gene INI-1. [31]

Breast cancer in situ

Locally invasive breast cancer
More commonly presents as a breast lump with or without nipple inversion, discharge, or tenderness.
Mammographic microcalcifications may be pure ductal carcinoma in situ (DCIS) or have an invasive component, which can be detected on excisional biopsy. [35]Lesions are not confined to the duct but have invaded surrounding tissue.
Atypical hyperplasia
Difficult to distinguish clinically, as asymptomatic.
Atypical hyperplasia on pathology.
Fibroadenoma
Presents as a breast lump on examination.If lump is palpable, it is typically freely mobile.
Mammographic calcifications that are large, are round, have sharp edges, and are diffuse are typically benign. [35]
Breast cyst
Most commonly presents as a breast lump and tenderness.May occur in association with menstrual cycle.
Mammographic calcifications that are large, are round, have sharp edges, and are diffuse are typically benign. [35]

Breech presentation

Transverse lie
Fetus lies horizontally across the uterus with the shoulder as the presenting part.Similar predisposing factors such as placenta praevia, abnormal amniotic fluid volume, and uterine anomalies, although more common in multiparity. [1] [2] [27]
Clinical examination and fetal auscultation may be indicative.Ultrasound confirms presentation.

Brief psychotic disorder

Schizophrenia
Period of psychosis lasts for >1 month. Diagnosis based on patient hx and FHx and medical records.
Clinical diagnosis.
Delusional disorder
Period of psychosis lasts for >1 month. Diagnosis based on patient hx and FHx and medical records.
Clinical diagnosis.
Major depressive disorder with psychotic features
Period of psychosis lasts for >1 month. Diagnosis based on patient hx and FHx and medical records.
Clinical diagnosis.
Recent substance use
Report from patient or family of recent substance use. Physical examination findings may be consistent with effects of substance.
Blood and/or urine toxicology: positive for specific substance/s.
Seizure disorder
History of seizures.
EEG: typical findings according to seizure type.MRI and CT brain scan: may demonstrate causative neurological lesions.
Syphilis (quaternary)
History of sexual contact with infected person.CNS involvement: may be associated with cranial nerve palsy, stroke, dementia, sensory loss, Argyll Robertson pupil.
Serum and CSF: VDRL, RPR, Treponema pallidum haemagglutination (TPHA), FTA positive.
Sarcoidosis
CNS involvement: may be associated with palsies of cranial and peripheral nerves, seizures, meningitis (granulomatous). Pituitary involvement can cause diabetes insipidus.Pulmonary features include dyspnoea and cough.
Serum ACE activity: increased.MRI and CT brain scan: space-occupying lesions.CXR: bihilar lymphadenopathy, pulmonary infiltrates.
Lung cancer
CNS metastases: focal neurological signs.Paraneoplastic syndrome: can include neuropathy, myopathy, cerebellar degeneration.Pulmonary features include dyspnoea, cough, haemoptysis.
MRI and CT brain scan brain: metastasesCXR and CT chest scan: mass, coin lesions, pleural effusion, hilar lymphadenopathy.
Thyrotoxicosis
Signs include tachycardia, tremor, thyroid enlargement.
TSH: reduced.Free T4 and free T3: elevated.
Head trauma
History of head trauma. May be accompanied by focal neurological signs.
MRI and CT brain scan: may demonstrate focal sequelae of trauma such as haematoma, skull fracture, cerebral oedema.

Bronchiectasis

COPD
Rhonchi in combination with diminished breath sounds, characterising COPD, are not found in bronchiectasis.In bronchiectasis, rhonchi may be auscultated, but with additional inspiratory squeaks and crackles.
Chest CT may be normal or show emphysema in COPD, as opposed to the characteristic abnormal results found in bronchiectasis (thickened, dilated airways with or without air fluid levels, varicose constrictions along airways, ballooned cysts at the end of a bronchus, and/or tree-in-bud pattern). Patients with COPD may also develop bronchiectasis.
asthma
Inspiratory squeaks and crackles, often present in bronchiectasis, are not present in asthma.Airflow obstruction is often reversible in asthma.
Chest CT may be normal or show mosaicism in asthma, as opposed to the characteristic abnormal results found in bronchiectasis (thickened, dilated airways with or without air fluid levels, varicose constrictions along airways, ballooned cysts at the end of a bronchus, or tree-in-bud pattern).
pneumonia
Patients with pneumonia describe symptoms of short duration (7 to 10 days), as opposed to years in bronchiectasis.Auscultation findings (rhonchi, wheezing, crackles) may be similar in bronchiectasis and pneumonia, especially multi-lobar pneumonia.
CXR and chest CT results in pneumonia are quite variable and often depend on aetiology.In bronchiectasis, there is characteristic dilatation of bronchi without airway thickening.
chronic sinusitis
The inspiratory squeaks and crackles found in bronchiectasis are uncommon in chronic sinusitis.
CXR and chest CT are normal in chronic sinusitis. Sinus CT shows opacification of the involved facial sinus in chronic sinusitis.

Bronchiolitis

Bacterial pneumonia
Pneumonia is much less common in this age group than bronchiolitis.Infants with pneumonia generally have higher fever (≥40°C) than with bronchiolitis.Wheezing is not a common finding in pneumonia.
An FBC may demonstrate leukocytosis and neutrophilia.The presence of infiltration on chest x-ray would increase the suspicion of pneumonia.
Chlamydia pneumoniae pneumonia
The mothers may have a history of vaginal chlamydial infection.Most infants with C pneumoniae infection have a history of neonatal conjunctivitis.The clinical course of C pneumoniae pneumonia is usually subacute and not associated with upper respiratory tract infection.Patients are usually afebrile. The cough of C pneumoniae has a distinctive staccato-like quality. Crackles are more common than wheezes in C pneumoniae.
Eosinophilia is a feature of C pneumoniae that is not seen in bronchiolitis.C pneumoniae can be diagnosed by culture or antigen detection from nasopharyngeal secretions.
Cystic fibrosis (CF)
CF is usually associated with symptoms and signs of pancreatic insufficiency, such as steatorrhoea, failure to thrive, and fat-soluble-vitamin deficiencies.A FHx of CF is common in affected infants.CF lung disease usually presents as chronic cough.It is insidious in onset and not associated with upper respiratory tract symptoms.
Measurement of sweat chloride by quantitative pilocarpine iontophoresis will be elevated (>60 mmol/L) in almost all infants with CF.
Laryngotracheobronchitis (croup)
A viral infection of the upper airways, often caused by parainfluenza virus.Characterised by fever, inspiratory stridor, and a barking cough.Symptoms often worsen at night.
Diagnosis is usually clinical.Sub-glottic narrowing may be seen on an AP neck radiograph; however, this investigation is rarely indicated.

Bronchiolitis obliterans organising pneumonia

Nodular sarcoidosis
No particular differentiating signs and symptoms.
CXR may show showing enlarged hilar lymph nodes.
Chronic eosinophilic pneumonia (CEP)
No particular differentiating signs and symptoms.
High-resolution chest CT scan (HRCT) in CEP shows peripheral ground glass opacities with sparing of the central portions of the lungs.FBC with differential may show increased blood eosinophils.
Bronchiolitis interstitial pneumonia (BIP)
Shortness of breath will be progressive and crackles will persist while the patient is receiving corticosteroid therapy.
Lung biopsy shows interstitial fibrosis distant from the bronchiolar disease. BIP may show disruption of lung architecture with traction bronchiectasis and honeycombing. [37] .
Non-specific interstitial pneumonia (NSIP)
Shortness of breath will be progressive and crackles will persist while the patient is receiving corticosteroid therapy.
HRCT in NSIP shows traction bronchiectasis and honeycombing. [38]
Idiopathic pulmonary fibrosis with a usual interstitial pneumonia (UIP) pattern
Patients with UIP will have progressive shortness of breath and increasing degree of bilateral crackles.
HRCT shows linear opacities at the lung bases, traction bronchiectasis, and subpleural honeycombing.
Wegener's granulomatosis
Patients with Wegener's granulomatosis may have nasal-sinus and renal symptoms.
HRCT shows bilateral multiple cavitary lesions.
Acute interstitial pneumonia
Symptoms and findings same as rapidly progressive BOOP.
HRCT may show disrupted lung architecture with traction bronchiectasis and early honeycombing.
Pulmonary metastasis and primary adenocarcinoma
Symptoms of cough and shortness of breath progress when the patient is treated with corticosteroids.
Kerley B lines occur in carcinomatosis.Chest x-ray may detect a solitary pulmonary nodule, mass, pleural effusion, lung collapse, or mediastinal or hilar fullness.Chest CT scan shows size, location, and extent of primary tumour; evaluates for hilar and/or mediastinal lymphadenopathy and for distant metastases.Sputum cytology shows malignant cells in sputum.Bronchoscopy shows endobronchial lesions.Biopsy shows confirmation of malignancy.
Pulmonary tuberculosis
Symptoms of cough, haemopytsis, and shortness of breath become progressive with corticosteroid treatment.
HRCT shows upper lung non-layering cavitary lesions.
Community-acquired pneumonia
Symptoms of cough, sputum production, and fever subside with antibiotic therapy.
CXR shows patchy infiltrates beginning to resolve with antibiotic therapy.
Bronchioloalveolar cell carcinoma
Symptoms will be similar for bronchioloalveolar cell carcinoma and BOOP.
There may be a pleural tag and the process bending or crossing the fissures on HRCT.

Brucellosis

Tuberculosis (TB)
History of HIV infection or immunosuppression may be present. Pulmonary findings are common and include tachypnoea, decreased breath sounds, crackles, and dullness to percussion; extrapulmonary findings are dependent on the site involved. Lymphadenopathy is common in all age groups.Deformity of the spine with or without long-tract CNS signs suggests TB, as does joint destruction.
Positive stains for acid-fast bacilli and/or culture of TB organisms.Biopsy of affected organ reveals caseating granulomas.X-rays show destructive changes with deformity of spine.
Malaria infection
Tertian or quartan fever pattern typical. Renal failure and haemorrhagic complications can occur.
Peripheral blood smear reveals Plasmodium parasite; malaria antigen detection tests positive.
Typhoid infection
Patients usually appear toxic, with sustained high fever.An erythematous maculopapular rash that blanches on pressure may be present.
Blood or bone marrow culture results in isolation of Salmonella typhi or S paratyphi.
Septic arthritis
Risk factors for infection, such as intravenous drug use and immunocompromise, may be present.Hot, swollen tender joint(s) present on physical examination.
Synovial fluid microscopy shows neutrophils and may show gram-positive organisms (or acid-fast bacilli) but not brucellae.Culture of blood and/or synovial fluid positive for causative organism.
Rheumatoid arthritis (RA)
Symmetric polyarthritis commonly affecting the small joints of the hands and feet. RA does not affect the lumbar spine or sacroiliac joints.
Rheumatoid factor and anti-cyclic citrullinated peptide antibodies may be positive in RA. Hand radiographs reveal typical erosive changes.
Systemic lupus erythematosus
Symmetric polyarthritis often affecting distal joints, accompanied by skin rashes, hair loss, hepatosplenomegaly, retinitis, neuropsychiatric problems, and serositis (e.g., pleural effusion).
Positive antinuclear antibody; positive anti-ds-DNA and anti-Smith antibodies confirm diagnosis.
Behcet's syndrome
Common in Middle Eastern and Mediterranean populations.Presence of oral ulcers necessary for diagnosis.Genital ulcers, skin lesions, and eye lesions are common.
Pathergy testing results in formation of pustule within 48 hours; negative serological tests and cultures for brucellosis.
Gout
Fever absent. Involved joints are warm, red, and swollen. Usually, there is considerable joint tenderness and limited range of movement due to pain.Hard subcutaneous nodules (tophi) over the extensor surface of the joint, especially over the elbows, knees, and Achilles tendons, may be present. Tophi may also be evident over the dorsal aspects of the hands and feet and in the helix of the ears.
Synovial fluid polarising microscopy will reveal strongly negative, birefringent, needle-shaped crystals.
Pseudogout
Fever absent. Involved joints are warm, red, and swollen. Usually, there is considerable joint tenderness and limited range of movement due to pain.
Calcium pyrophosphate dihydrate crystals in synovial fluid can be small, sparse, and difficult to find.
Osteoarthritis
Fever absent. Patients present with joint pain and stiffness that is typically worse with activity.
Plain film x-ray of affected joint usually demonstrates new bone formation (osteophytes), joint space narrowing, and subchondral sclerosis and cysts.
Granulomatous hepatitis
Granulomata in the liver are associated with a number of disorders. Infectious disorders are the most important: bacterial (e.g., TB and other mycobacterial infections, tularaemia, actinomycosis), fungal (e.g., histoplasmosis, cryptococcosis, blastomycosis), parasitic (e.g., schistosomiasis, toxoplasmosis, visceral larva migrans), less common viral infections (e.g., infectious mononucleosis, cytomegalovirus), and numerous others (e.g., Q fever, syphilis, cat-scratch disease).Sarcoidosis is the most important non-infectious cause. Hepatic granulomas can also occur in polymyalgia rheumatica and other collagen-vascular diseases, and in Hodgkin's disease and some other systemic conditions.
Histology reveals conspicuous and frequent granulomas (caseating or non-caseating).
Lymphoma
Usually presents with a painless mass in the neck, axilla, or inguinal region.Typical examination findings include lymph node enlargement, with or without tenderness, and hepatosplenomegaly.
Core biopsy of lymph node or suspected tissue shows abnormal proliferation of lymphocytes.
HIV infection
History of high-risk behaviour (IV drug use, multiple sexual partners, unprotected sexual intercourse). Herpes zoster, oral candidiasis, pronounced weight loss, and/or opportunistic infection (e.g., Pneumocystis jirovecii, TB) may be present.
HIV antibodies positive; may be negative in early disease.
Mumps
More common in children and young adults.Orchitis is usually bilateral and typically accompanied by parotid gland swelling.
Positive serum amylase tests (salivary or pancreatic origin); positive serum mumps IgM.

Bruxism

Oromandibular dystonia
Slow, twisting, repetitive muscle spasms that affect the mandible, tongue, and lips. [26] Often associated with dystonia of the neck muscles (cervical dystonia/spasmodic torticollis), eyelids (blepharospasm), or larynx (spasmodic dysphonia). Sleep bruxism can also be present.
No differentiating tests. Clinical diagnosis.
Huntington's disease
Hereditary neurodegenerative condition characterised by irregular, unpredictable choreic body movements. [26] Sleep bruxism may also be a feature.Neurological evaluation identifies characteristic cognitive impairment (e.g., concentration impairment, task apathy, and anxiety), behavioural features (e.g., irritability, impulsivity), and motor features (e.g., chorea, twitching/restlessness, bradykinesia/rigidity).
Genetic testing confirms gene with an expanded trinucleotide CAG repeat (the mutant allele).
Tourette's syndrome
Repetitive, irregular, stereotyped, suppressible movements (tics) of the eyes, face, and neck. May occur during light non-rapid-eye movement (non-REM) sleep, sleep stage shifts, and micro-arousals and awakenings. [26]
No differentiating tests. Clinical diagnosis.
Hemifacial spasms
Unilateral, non-epileptic twitches of the face also during sleep. [26]
Needle EMG shows irregular, brief, high-frequency bursts (150-400 Hz) of motor unit potentials, which correlate with clinically observed facial movements.
Parkinson's disease
Multi-system neurological syndrome characterised by hypokinetic movements due to muscle stiffness and resting tremor. Caused by degeneration of the dopaminergic system. Swallowing difficulties and drooling may persist during sleep, whereas resting orolingual tremor is absent. [26]
Dopaminergic agent trial shows improvement in symptoms.
Tardive dyskinesia
Neuroleptic-induced abnormal oromandibular movement disorder eventually associated with sleep bruxism. [26] May feature any or all of movement of the lips and tongue (grimacing, smacking, pursing, sticking out the tongue), rapid blinking, impaired finger movement or 'fluttering', rapid movements of the arms, toe-tapping, moving the leg up and down, twisting and bending of the torso (in extreme cases).
No differentiating tests. Clinical diagnosis.
REM-behaviour disorder
Acting out dramatic and/or violent dreams, so may involve limbs. Often involves grunting or shouting. Usually seen in men ≥60 years old.
Polysomnographic video recording shows increase in muscle tone associated with the EEG pattern of REM sleep (in contrast to the EEG pattern of REM sleep associated with an absence of muscle tone in healthy individuals). Video shows body movements coinciding with the EEG pattern of REM sleep.

Budd-Chiari syndrome

Sinusoidal obstruction syndrome (SOS) (veno-occlusive disease)
Usually occurs in the setting of recent bone marrow transplant.According to Seattle criteria, 2 of 3 of the following findings occurring within 20 days of transplantation can diagnose SOS: bilirubin >34.2 micromol/L (2 mg/dL); hepatomegaly or RUQ pain of liver origin; >2% weight gain due to fluid accumulation. [43]
Bilirubin >34.2 micromol/L (2 mg/dL).Plasma plasminogen activator inhibitor-1 level above 100 nanograms/mL. [44]Detection of reverse blood flow in a segment of portal vein by colour-Doppler sonogram is useful for early diagnosis of veno-occlusive disease. [45]Liver biopsy: early histological findings are narrowing of the sublobular and central veins due to subendothelial oedema, possibly secondary to disruption of sinusoidal endothelial cells (SEC) barrier and congestion of hepatic sinusoids, surrounded by pale necrotic hepatocytes. [46]
Fulminant hepatic failure due to other aetiologies
Often clinically indistinguishable.May have history of alcohol abuse, risk factors for viral hepatitis (e.g., intravenous drug user, blood transfusion, travel to endemic areas), or family history of liver disease (e.g., Wilson's disease). Drugs such as paracetamol and halothane may cause acute liver failure.
Viral serology (hepatitis A virus IgM, hepatitis E virus IgM, HBsAg, anti-HBc IgM, hepatitis delta IgM, and CMV IgM): positive.Serum copper and ceruloplasmin levels: abnormal in Wilson's disease.Drug levels elevated (e.g., paracetamol).ANA, acid sphingomyelinase, and liver/kidney microsomal antibody 1 and 2: elevated.Normal-appearing hepatic veins and portal vein shown with imaging.
Congestive hepatopathy
History of exertional dyspnoea, orthopnoea, and angina.Jugular venous distention, heart murmurs, rales, tender hepatomegaly, sometimes massive, with a firm and smooth liver edge, and peripheral oedema. Jugular venous distention with hepatojugular reflux may be present. Splenomegaly is uncommon.
Elevation of total serum bilirubin level, most of which is unconjugated; serum aminotransferase levels show a mild elevation unless cardiac output is impaired (extremely high); prothrombin time may be mildly abnormal; albumin level may be decreased; serum ammonia level may be elevated.Echocardiogram: depressed and dilated left and/or right ventricle with low ejection fraction; may reveal underlying cause.
Tricuspid regurgitation
History of CAD/previous MI, infective endocarditis, or carcinoid disease.Lower left parasternal systolic murmur that increases on inspiration. Jugular vein distention with hepatojugular reflux, peripheral oedema, pulsatile hepatomegaly (very characteristic feature).
Echocardiogram: ventricular and annular dilation, regurgitant jet on Doppler.ECG: atrial flutter/fibrillation; evidence of previous myocardial infarction.
Constrictive pericarditis
History of tuberculosis, transmural MI, cardiac surgery, neoplasm, viral or bacterial infection, uraemia, dialysis treatment, radiotherapy, or systemic autoimmune disorders.Sharp, stabbing, pleuritic, or aching chest pain. Trapezius ridge pain.Jugular venous distention, Kussmaul's sign (jugular venous distension rises with inspiration), pulsus paradoxus, pericardial knock. Pericardial rub described as high-pitched or squeaky; best heard at the left sternal edge with the patient leaning forwards at end-expiration.
ECG: low voltage with upwards concave ST segment elevation globally and PR depressions.Echocardiogram: thickened pericardium, pericardial effusion, and limitation to ventricular filling.Calcification of pericardium sometimes seen on CXR.Chest CT: pericardial effusion or the pericardial cavity completely replaced by granulation tissue in chronic cases.Right and left heart catheterisation with haemodynamic evaluation may be required to confirm the diagnosis.
Right atrial myxoma
Systolic murmur loudest in inspiration, with tumour 'plop', may be heard.
FBC: Hb and Hct decreased; leukocytosis, thrombocytopenia.Echocardiogram: atrial mass seen.CT or MRI: differentiation between mass and thrombus.

Buerger's disease

Embolic disease
Often affects only 1 limb but can affect more. Recent chest pain suggesting a myocardial infarction.
In embolic disease, an echocardiogram may show a valve lesion or thrombus; ECG and troponin may show evidence of myocardial ischaemia.Echocardiogram, ECG, and troponin blood tests show no dysrhythmia and no evidence of recent myocardial infarction in Buerger's disease.Duplex imaging may reveal the embolised thrombus.
Hypercoagulable state
Multiple limbs affected. Known history or family history of thrombophilia disease.
Coagulation profile: PT, PTT, and INR may be elevated.Thrombophilia screen: may be positive for protein C, protein S, or anti-thrombin III deficiencies.
Raynaud's phenomenon (RP)
Painful extremities associated with cold weather exposure and a lack of skin loss.Onset of symptoms with limb immersion in cold water.
ANA, FBC, ESR, metabolic panel, and urinalysis may be normal in primary RP and abnormal in secondary RP.
Atherosclerosis
Claudication history. Absent femoral pulses.Associated with hypercholesterolaemia, hypertension, and diabetes.
Atherosclerotic plaques seen on radiological imaging of arteries.
Rheumatoid vasculitis
Usually known long-standing rheumatoid arthritis.Active symmetric arthritis lasting >6 weeks, most commonly affecting the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsalphalangeal (MTP) joints.Skin rash is the most common vasculitic manifestation.
Rheumatoid factor positive in up to 70% of cases.Anti-cyclic citrullinated peptide (anti-CCP) positive in 70%-80% of cases.Joint x-rays reveal erosions.
Systemic lupus erythematosus
Patients may have skin manifestations including malar, photosensitive, or discoid skin rash, mouth or nose ulcers, or diffuse patchy alopecia.Other features include constitutional symptoms (e.g., fever, fatigue, weight loss), lymphadenopathy, musculoskeletal symptoms, Raynaud's phenomenon, and symptoms of CNS, gastrointestinal cardiopulmonary, or haematological involvement.
Anti-nuclear antibodies, dsDNA, and Smith antigen are positive.
Wegener's granulomatosis
Classic triad consists of upper and lower respiratory tract involvement and pauci-immune glomerulonephritis, producing renal symptoms. Involvement of cutaneous, ocular, musculoskeletal, and peripheral nervous system tissue is also common.Constitutional symptoms include fatigue, malaise, fever, night sweats, anorexia, and weight loss.
Positive cANCA (cytoplasmic pattern on immunofluorescence testing) combined with positive proteinase 3 antibody testing byenzyme immunoassay (EIA).Positive pANCA (perinuclear pattern on immunofluorescence testing) combined with positive myeloperoxidase antibody testing by EIA.
CREST syndrome
Acronym for calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia.Disease typically limited to distal upper and lower extremities; may involve face and neck.Oesophageal dysmotility produces dysphagia and GERD. Sclerodactyly produces bright shiny skin of hands and feet.Other features include dilated nailbed capillaries, symmetrical swelling of the fingers with reduced range of motion, contractures affecting joints in the hand, claw hand deformities, digital ulcers, and carpal tunnel syndrome.
Anti-centromere antibody may be positive and is strongly suggestive of the disease.Serum anti-nuclear antibody may be positive but is not specific.Serum extractable nuclear antigens may be positive.CBC with peripheral fragmentation of red blood cells is associated with systemic disease.Serum creatinine elevated in presence of renal crisis.

Bulimia nervosa

Eating disorder not otherwise specified (EDNOS)
Characterised by disordered eating that affects normal functioning. Patients may have one or a combination of behaviours, including restricted eating; over-exercising; rumination about food; bingeing; purging; or laxative, enema, suppository, or diuretic use.If the complete definition of bulimia nervosa or anorexia nervosa is met, that is the diagnosis.
No differentiating tests.
Anorexia nervosa, binge-eating/purging subtype
Both bulimia nervosa and anorexia nervosa binge/purge subtype have the binge and purge behaviour. However, anorexia nervosa has as its key element a pathological fear of fat and weight gain leading to unhealthy weight loss. Bulimia nervosa does not.Body mass index and body fat are low in anorexia nervosa but not in bulimia nervosa. Patients with anorexia nervosa are much more likely to have hypothermia, bradycardia, and anaemia.
No differentiating tests.
Binge-eating disorder
Binge-eating occurs without any compensatory behaviours. Most patients with binge-eating disorder are obese. Most patients with bulimia nervosa are within normal weight range.
No differentiating tests.
Kleine-Levin syndrome
Presents with irregularly recurring hypersomnia episodes in men aged 10 to 25 years. It is associated with psychiatric symptoms that include bingeing, sexual behavioural disorders, personality disorders, and mood disorders. [67] It is very rare and usually occurs in Jewish males. Hypersomnia is not typical of bulimia nervosa. [68]
No differentiating tests.
Major depressive disorder (MDD)
Occurs concurrently in ≥50% of cases of bulimia nervosa. Overeating can occur in MDD but the compensatory behaviours are fewer or absent.Depressed mood, reduced interest, weight change, insomnia, agitation, fatigue, and impaired concentration can be seen in both MDD and bulimia nervosa. Early morning wakening, guilt, and thoughts of death suggest MDD.
No differentiating tests.
Other psychiatric disorders, including borderline personality disorder
Anxiety, substance abuse/dependence, and personality disorders are common in patients with bulimia nervosa.Some patients may complain of or incorporate eating disordered behaviours to access treatment facilities available only to patients with eating disorders. These patients do not have a characteristic history (e.g., they may be able to go for periods of time without bingeing and purging).Comorbid disorders are differentiated by the degree to which their symptoms have an independent course and severity from the bulimia nervosa. Concurrent substance abuse/dependence may become apparent only because of drug withdrawal and impaired attendance, cognition, or behaviour.
No differentiating tests.
Hyperemesis gravidarum
Weight loss greater than 5% may suggest hyperemesis gravidarum. In bulimia nervosa, there may be a precedent history; bulimia typically improves with pregnancy in about two-thirds of cases (while worsening in about one-third).
Diagnosis is clinical.Weight loss due to hCG-induced hyperthyroidism needs to be excluded. In these cases, hCG is elevated, TSH is low, and T4 is elevated.Presence of chromosomal abnormalities, multiple gestations, gestational trophoblastic disease or hypdrops fetalis increases the risk of hyperemesis.

Bullous pemphigoid

Pemphigus vulgaris
Difficult to distinguish clinically. Skin lesions are usually erosive and do not form tense bullae. Oral lesions more common.
Direct immunofluorescence testing for IgG, C3, or both detects a broad linear band on the surface of epidermal keratinocytes in the suprabasilar region of the epidermis.
Epidermolysis bullosa acquisita
The inflammatory form of epidermolysis bullosa acquisita may mimic bullous pemphigoid closely. Blisters tend to appear both spontaneously and as a result of trauma, predominantly on trauma-exposed body surfaces. Lesions heal with significant scarring. [29]
Salt-split skin test for indirect immunofluorescence testing detects linear deposits of IgG at the base of the blister cavity (dermal side). Direct immunofluorescence is also necessary. [29]
Linear IgA dermatosis
Linear IgA dermatosis has a bimodal age of onset, as opposed to the predominating older population in bullous pemphigoid. In linear IgA dermatosis, clear and/or haemorrhagic vesicles or bullae arise on normal, erythematous, or urticarial skin with a characteristic 'string of pearls' appearance. [29]
Definitive diagnosis is made by direct immunofluorescence, which reveals linear deposition of IgA along the dermal-epidermal junction. [29] The salt-split skin test for direct immunofluorescence testing, simple to perform, is also necessary to differentiate these diagnoses.
Dermatitis herpetiformis
Dermatitis herpetiformis presents with symmetrical, grouped excoriations; erythematous, urticarial plaques; and papules with vesicles located on the extensor surfaces of the elbows, knees, buttocks, and back. Intensely pruritic, the vesicles are often excoriated to erosions by the time of examination. In bullous pemphigoid, lesions may sometimes appear in the mouth, which is not found in dermatitis herpetiformis.
Diagnosis requires direct immunofluorescence of a skin biopsy specimen showing deposition of IgA in a granular pattern in the dermal papillae. [30]
Porphyria cutanea tarda
Patients present with serous or haemorrhagic vesicles or bullae on sun-exposed areas of the body, which include the face, dorsal hands, and extensor forearms. The lesions are often painful and heal slowly, with atrophic scars, milia, and post-inflammatory hyperpigmentation. [2] Lesions in bullous pemphigoid tend to be painless and typically do not present haemorrhagic.
The characteristic direct immunofluorescence test reveals C3, IgG, and IgM deposition in the capillary walls and at the dermoepidermal junction. On urinalysis, the porphyrin level is usually >1000 micrograms in a 24-hour period. A reddish-pink colour is seen when the urine is examined with a Wood lamp. [2] Routine histology of a lesion demonstrates the presence of a sub-epidermal blister with little inflammatory infiltrate in the dermis. A haematological examination typically shows elevated levels of iron, ferritin, and transaminases.
Erythema multiforme
Erythema multiforme is an acute self-limited eruption, the hallmark of which is the iris or target lesion. Bullous pemphigoid does not have ocular involvement.
Presence of typical target lesions and the histopathological finding of interface dermatitis are diagnostic of erythema multiforme. The direct immunofluorescence test may be negative or only detect clumpy deposits of IgM at the dermal-epidermal junction, reflecting necrotic keratinocytes as a result of the interface dermatitis.
Urticaria
Urticaria is a common, variably pruritic eruption of transient erythematous, oedematous papules and plaques that vary in size and shape. Bullous pemphigoid may initially present with urticarial areas that later develop bullous lesions, but plaques do not appear.
There are no routine studies for diagnosis. Biopsy is usually not needed and it would not differentiate from the prodromal, non-bullous phase of bullous pemphigoid, although the latter often has a denser inflammatory cell infiltrate greatly dominated by eosinophils.

Bursitis

Medial meniscopathy
May be confused with anserine bursitis.McMurray test: usually positive in meniscal disease and negative in bursitis. Patient lies supine; leg is rotated on the thigh with the knee fully flexed. The physician grasps the patient's foot. The leg is flexed to 90° while the foot is maintained first in full internal rotation and then rotated in full external rotation. A click occurs and the patient feels pain if a meniscal tear is present.Apley grind test: usually positive in meniscal disease and negative in bursitis. Patient lies prone; foot is rotated externally and knee flexed to 90°. Foot rotated internally and knee extended. The tibia is then compressed into the knee joint while externally rotating the foot. If this increases the pain, test is positive, indicating meniscal damage.Bounce home test: usually positive in meniscal disease and negative in bursitis. With the patient lying supine, the surgeon grasps the foot and completely flexes the knee. The knee is then passively allowed to extend. The knee should extend completely or bounce home into extension with a sharp endpoint. Test is positive when full extension cannot be attained.
MRI: shows a meniscal tear, communicating with its superior and/or inferior surfaces or inner margin, on >1 slice. Meniscal subluxation is defined as protrusion over the edge of the tibial plateau seen at the level of the body of the meniscus.
Medial compartment osteoarthritis
May be confused with anserine bursitis.Medial knee osteoarthritis is defined as pain or stiffness for most days of the preceding month and osteophytes at the medial joint margin of the tibiofemoral joint.
Weight-bearing radiographs of the knees: shows medial joint space narrowing, osteophytes, subchondral bone cysts, and sclerosis.
Baker's cyst
May be confused with anserine bursitis.Often asymptomatic. The cyst may rupture or leak, causing swelling and pain in the popliteal region.
Ultrasound scan: demonstrates a fluid-filled cystic mass in the popliteal region.MRI: shows an oval-shaped, fluid-filled, well-defined mass posterior to the knee joint.
Medial collateral ligament damage
May be confused with anserine bursitis.Valgus stress test is usually positive in medial collateral ligament disease and negative in bursitis. The patient lies supine. The physician places one hand on the lateral aspect of the knee joint and the other hand on the medial aspect of the distal tibia. A valgus stress is applied with the leg flexed to 30°. If the knee joint abducts more than the uninjured leg, the test is positive.
MRI scan: shows increased signal within the ligament itself without an associated knee joint effusion (unless there is another injury such as an associated ACL tear or patellar dislocation).
Soft-tissue infection
Clinically similar to any bursitis, with pain, erythema, and swelling. May have spreading cellulitis.
MRI: a reticulated pattern of abnormal signal intensity in the subcutaneous tissue on both T1-weighted and fluid-sensitive sequences. When intravenous contrast is administered, the subcutaneous tissues will have a reticulated pattern of enhancement. Non-infective oedema may have similar signal characteristics but without enhancement.X-ray/CT: fasciitis is an infection of the deep or superficial fascia. Soft-tissue gas is a suggestive feature of necrotising fasciitis.
Local bone tissue tumours
Can be clinically similar to any local bursitis, with pain, swelling, and erythema.
X-ray: abnormal bone mass can be readily identified. Further imaging may not be required.MRI: useful to delineate anatomical boundaries and may demonstrate soft-tissue involvement.Bone scan: normally shows increased uptake, although some tumours show decreased uptake. Done in combination with x-ray or MRI.
Spinal stenosis
May be confused with subtrochanteric bursitis.Neurogenic claudication: pain extending from the back into the buttocks and thigh, and sometimes into the lower leg. The pain is exacerbated by lumbar extension and improves with lumbar flexion.A sensory or motor deficit is present in about half of patients with symptomatic lumbar stenosis.Romberg's manoeuvre: patient stands with eyes closed and is observed for imbalance. This may reveal a wide-based gait and unsteadiness, reflecting involvement of proprioceptive fibres in the posterior columns.
X-ray: narrowing may occur in the central spinal canal, in the area under the facet joints (subarticular stenosis), or more laterally, in the neural foramina. Can demonstrate the extent of disc-space narrowing, end-plate sclerosis, and facet-joint hypertrophy. The neural foramina may reveal osteophytes, suggesting foraminal stenosis.MRI/CT: can confirm the presence of spinal stenosis, as a reduction in the cross-sectional area of the central canal and neural foramina.
Lumbar radiculopathy
May be confused with subtrochanteric bursitis.A sharp or dull, burning pain in the back, radiating into the leg (sciatica).Pain is exacerbated by bending forwards or sitting and relieved by lying down and sometimes by walking. Typical presentation is pain and sensory loss.Tests of Lasegue, Wasserman, and Valsalva are usually positive in lumbar radiculopathy and negative in bursitis.Lasegue test: usually positive in lumbar radiculopathy and negative in bursitis. With the patient lying supine, the surgeon flexes the leg to 90° at the hip and knee. The knee is slowly extended, which produces radiating pain.Wasserman test: usually positive in lumbar radiculopathy and negative in bursitis. The patient lies prone and the physician slowly extends the hip. Accentuation of pain in the anterior thigh suggests a high lumbar (L2, L3) radiculopathy.Valsalva test: usually positive in lumbar radiculopathy and negative in bursitis. This manoeuvre increases intrathecal pressure, which accentuates radicular pain in the presence of spinal nerve compression and inflammation.
MRI: reveals structure of the lumbosacral spine and nerve roots. Imaging results need to be interpreted in the context of clinical symptoms and signs.Needle electromyography: can diagnose compressive and non-compressive radiculopathies and provides a measure of severity of radiculopathic disease.
Osteoarthritis of the hip
May be confused with subtrochanteric bursitis.Hip pain or stiffness in the groin and hip region on most days of the preceding month.Often a loss of internal rotation initially.
X-ray: shows femoral or acetabular osteophytes and/or axial joint space narrowing.
Osteonecrosis of the hip
May be confused with subtrochanteric bursitis.Hip pain and/or stiffness in the groin and hip region.
X-ray: can demonstrate advanced stages of osteonecrosis characterised by sclerosis, lucency, and flattening of the femoral head.MRI: shows subchondral lesions of variable signal intensity outlined by a low-signal rim on T1-weighted images along the anterosuperior aspect of the femoral head. A more specific sign is the double-line sign (an outer low-intensity rim and an inner high-intensity band) on T2-weighted images.
Stress fracture of the hip
May be confused with subtrochanteric bursitis.Hip pain and/or stiffness in the groin and hip region.
X-ray: may demonstrate a stress fracture, but this is often missed on plain films.MRI: is the most sensitive modality to detect and characterise stress fracture of the hip.
Rotator cuff tendinopathy
Clinically indistinguishable from subacromial bursitis. Many patients with a rotator cuff tendinopathy have a subacromial bursitis as well.
MRI: shows an increased signal within the tendon of the rotator cuff.
Rotator cuff lesions
Often clinically indistinguishable from subacromial bursitis. Many patients with rotator cuff tendinopathy have an associated subacromial (subdeltoid) bursitis. Usually, weakness accompanies pain. Pain with preserved strength is more suggestive of bursitis or tendinopathy.
MRI: shows an interruption of the signal within the tendon of the rotator cuff.
Calcific tendinopathy of the rotator cuff or Achilles tendon
Clinically indistinguishable from subacromial/retrocalcaneal bursitis.
X-ray: may show presence of a calcific deposit within the tendon of the rotator cuff or Achilles tendon.Ultrasound: can detect calcifications in the Achilles tendon as hyperechoic areas casting acoustic shadowing.MRI: demonstrates presence of a calcific deposit within the tendon.
Superior labrum anterior to posterior (SLAP) lesions of the long head of the biceps tendon
Often clinically indistinguishable from subacromial bursitis.O'Brien test: a positive result suggests an SLAP lesion. The arm is flexed to 90° with the elbow extended. The arm is adducted by 10° and the thumb pointed towards the floor. Downward pressure is applied by the examiner. The palm is then supinated and the procedure repeated. The test is considered positive if pain is elicited with the first manoeuvre and reduced or eliminated on supination.Speed test: a positive result suggests an SLAP lesion. The patient flexes his/her shoulder against resistance while the elbow is extended and forearm supinated. The test is positive when pain is localised to the bicipital groove. [15]
MRI: shows the presence of increased signal within the labrum extending to its surface. If contrast is used, it may be taken up into the labrum.
Subluxation of the long head of the biceps tendon
Clinically indistinguishable from subacromial bursitis but often associated with an injury to the subscapularis, which might be detected with the belly-press test or the lift-off test.Belly-press test: the patient presses the abdomen with the flat of the hand and attempts to keep the arm in maximal internal rotation. If subscapularis is impaired, the elbow drops back behind the trunk.Lift-off test: patients with subscapularis rupture will be unable to lift the dorsum of their hand off their back.
MRI: shows the presence of a subluxated long head of the biceps tendon.
Tendinopathy of the long head of the biceps tendon
Clinically indistinguishable from subacromial bursitis.
MRI: shows the presence of increased signal within the long head of the biceps tendon.
Haglund's deformity
May be confused with, or exist along with, retrocalcaneal bursitis.The pain generally emanates from the posterior aspect of the heel and is aggravated by active or passive motion.
Lateral x-ray: prominent posteriosuperior calcaneal process. The ossification is in the most proximal extent of the insertion of the tendon or as a spur off the superior portion of the calcaneus.Haglund's syndrome is a triad of insertional tendinopathy of the Achilles tendon, retrocalcaneal bursitis, and Haglund's deformity.
Tendinopathy of the main body of the Achilles tendon
May be confused with retrocalcaneal bursitis.Pain and swelling is localised around the tendon.
Ultrasound: most commonly focal or diffuse thickening of the Achilles tendon with focal hypoechoic areas.MRI: features include morphological findings of a fusiform tendon shape, anteroposterior tendon thickening, and convex bulging of the anterior tendon margin. Areas of increased signal within the tendon on T2-weighted sequences are thought to represent more severe areas of collagen disruption and partial tearing.
Sever's lesion
May be confused with retrocalcaneal bursitis.Pain at the heel, which frequently occurs before or during the peak growth spurt.
Lateral x-ray of the ankle: may show avulsion of the calcaneal apophysis. Can be normal despite significant apophysitis.
Pronator syndrome
May be confused with olecranon bursitis.Anterior elbow pain or proximal volar forearm pain. May occur with repetitive pronation and gripping activities.Tinel's sign over the anterior cubital fossa may be present.Sensory deficits in the radial three and a half digits of the hand on the affected side may be present.
Electromyography: can help to delineate the severity of damage to the median nerve.
Lateral epicondylitis (tennis elbow)
May be confused with olecranon bursitis.Tenderness to palpation over the origin of the extensor carpi radialis brevis tendon.
Clinical diagnosis.
Posterior interosseous nerve syndrome
May be confused with olecranon bursitis.Tenderness at the lateral epicondyle and distally at the site of the arcade of Frohse. Often pain reproducible with resisted supination and extension of the middle finger.
Clinical diagnosis.
Medial epicondylitis (golfer's elbow)
May be confused with olecranon bursitis.Tenderness to palpation just anterior to the medial epicondyle.Resisted wrist flexion and forearm pronation while the patient's elbow is in extension reproduces symptoms.
Clinical diagnosis.
Ulnar collateral ligament injury
May be confused with olecranon bursitis.Valgus stress of the elbow reproduces the symptoms.
MRI and CT arthrography are both 100% sensitive for diagnosing complete tears.
Cubital tunnel syndrome
May be confused with olecranon bursitis.Flexion at the elbow may reproduce or exacerbate symptoms. May have tenderness over the ulnar nerve posterior to the medial epicondyle. Tinel's sign is often positive in this location.
X-ray of elbow: can detect osteophytes in the cubital tunnel.EMG may help to localise the lesion.
Posterolateral elbow instability
Lateral pivot shift test evaluates the lateral collateral ligament complex. Patient lies down and arm is internally rotated and supinated; the elbow is flexed as axial and valgus pressure is applied. Very uncomfortable in an awake patient.
X-ray elbow: may show fractures, loose bodies, or osteochondritis dessicans.MRI may reveal injury to the lateral collateral ligament complex.

B LINEAGE NHL (BC, BLL AND DLCL)

Acute lymphocytic leukaemia
Clinically indistinguishable from AML.
Bone marrow biopsy, peripheral blood smear, immunophenotyping, and immunochemistry may be helpful in establishing the diagnosis.Blast cells are positive for deoxynucleotidyl transferase and lack staining for myeloperoxidase; also demonstrate presence of lymphoid markers.
Biphenotypic leukaemia
Palpable lymph nodes may be present.
The expression of antigens representing both the myeloid and lymphoid leukaemia in the leukaemic clone suggests biphenotypic leukaemia. Cytogenetics may show Philadelphia chromosome t(9:22).
Myelodysplastic syndrome
History of long-standing anaemia and transfusion dependence.
The distinction between high-risk myelodysplastic syndrome (MDS) and AML is artificial in that it is based on the numbers of blasts present. The estimation of blast counts can be difficult and is subjective. The blood film shows dysplasia in >10% of cells of any lineage and the bone marrow may show up to 19% blasts.Micromegakaryocytes and acquired Pelger-Huet (spectacle eye nucleus) neutrophils are specific for MDS. Associated chromosomal deletions or unbalanced chromosomal abnormalities, particularly of chromosomes 8, 7, and 5, are common. Complex cytogenetic changes may occur.The presence of dysplasia may suggest that AML has evolved from MDS.
Chronic myelogenous leukaemia blast crisis
There may be a history of preceding chronic myelogenous leukaemia (CML).
The peripheral blood film may be indistinguishable from AML but may have an excess of basophils and eosinophils.The presence of the Philadelphia chromosome t(9:22) (q34;q11) supports a diagnosis of CML but does not exclude Philadelphia chromosome-positive AML.Typically no other karyotypic abnormalities are present.
Myelofibrosis
Typically splenomegaly is present.
Blood film shows teardrop RBCs and a leukoerythroblastic film.Bone marrow biopsy shows reticulin fibrosis.
Aplastic anaemia
May have history of medications that cause aplastic anaemia, such as chloramphenicol and non-steroidal anti-inflammatory drugs.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Low percentage of blast cells in peripheral blood (<10%). Precursors are morphologically normal.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.Patients should also be evaluated for an underlying paroxysmal nocturnal haemoglobinuria and evidence of intravascular haemolysis (reticulocytosis, elevated serum lactate dehydrogenase, and indirect bilirubin, and decreased haptoglobin). A negative Coombs test is suggestive.
Drug-induced bone marrow failure
History of using medications that may cause pancytopenia such as chloramphenicol, methotrexate, and chemotherapeutic agents.Cessation of the implicated agent or administration of an antidote such as folic acid for methotrexate reverses the pancytopenia.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow will be hypocellular, and no excess of blasts are present.Megaloblastic erythropoiesis is seen with methotrexate.Bone marrow should be reassessed after holding medication.
Leukaemoid reaction
Recent history of haematopoietic growth factor treatment may be present.Appropriate treatment (i.e., stopping the growth factor) results in normalisation of the blood count.
Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.Bone marrow shows no excess of blasts but mature haematopoietic cells. Increased macrophage activity and toxic granulation of myeloid cell series may be present suggesting infections; Dohle bodies may also be seen in infections.
Vitamin B12 deficiency
May have a family history consistent with pernicious anaemia.Paresthesia is an early symptom.Glossitis and neurological signs, such as cognitive impairment or subacute combined degeneration (ataxia, decreased vibration sense, muscle weakness, and hyporeflexia), occur with severe deficiency.
Macrocytic anaemia will be present unless there is an associated iron deficiency.Peripheral blood smear shows megaloblastic changes.Serum vitamin B12 levels are low.

Calcium pyrophosphate deposition

Acute gouty arthritis
Presentation may be identical to that of acute CPP arthritis.More likely to affect small joints of the lower extremity, particularly the first metatarsophalangeal (MTP) joint.Onset is sudden and attack duration is frequently shorter than in acute CPP arthritis. [39]Risk factors for hyperuricaemia, such as renal insufficiency, are more common.
Synovial fluid microscopy is negative for CPP crystals and positive for urate crystals.
Acute septic arthritis
Presentation may be identical to that of gout.Patients are typically immunocompromised.
Synovial fluid microscopy is negative for CPP crystals.Positive Gram stains or fungal stains, and cultures of synovial fluid.
Milwaukee shoulder syndrome
Typically limited to the shoulders and knees. Effusions are large and, in the shoulders, fluid is often palpable. [40]
Synovial fluid microscopy is negative for CPP crystals.Alizarin red S staining of synovial fluid is positive for calcium phosphate crystals.X-rays show a severe destructive arthropathy, with loss of the rotator cuff, bony destruction, and multiple loose bodies.
Osteoarthritis
Typically affects large weight-bearing joints, the cervical and lumbar spine, and the base of the first MTP. In the hands, it involves the first carpometacarpal, DIP, and PIP joints.
Synovial fluid microscopy is negative for CPP crystals.X-rays show no evidence of cartilage calcification.
Rheumatoid arthritis
Joints flare simultaneously. Affected joints tend to be in a symmetrical pattern.
Synovial fluid microscopy is negative for CPP crystals.X-rays show typical changes of erosive rheumatoid arthritis.
Polymyalgia rheumatica
Patients complain of prolonged morning stiffness involving the hips and shoulders.This is typically symmetrical and accompanied by signs and symptoms of systemic inflammation, such as weight loss and malaise.There is usually little or no synovitis.
Synovial fluid microscopy is negative for CPP crystals.ESR is high.

Campylobacter infection

Salmonella gastroenteritis
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.Bloody diarrhoea is much less common with non-enteric Salmonella infections.
Stool culture: Salmonella organism.
Shigella gastroenteritis
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.
Stool culture: Shigella organism.
Yersinia gastroenteritis
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.Bloody diarrhoea is much less common with non-enteric Yersinia infections.
Stool culture: Yersinia organism.
Escherichia coli gastroenteritis
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.
Stool culture: E coli organism.
Gastroenteritis caused by Vibrio species
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.Bloody diarrhoea is much less common with non-enteric Vibrio infections.
Stool culture: Vibrio organism.
Listeria gastroenteritis
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.
Stool culture: Listeria organism.
Cholera
Symptoms not significantly different. Campylobacter infection often presents with more severe abdominal pain.
FBC: may have elevated Hct or neutrophil count.Serum lactate: elevated.ABG: acidaemia.Darkfield/phase-contrast microscopy of stool: large quantity of curved bacilli.Rapid dipstick testing of stool: positive.
Viral gastroenteritis in adults
Viral gastroenteritis often has upper GI symptoms, including nausea and vomiting. However, it can present with diarrhoea.
Basic metabolic profile (BMP): may have high Na or K; low Na; metabolic acidosis.Renal function: urea, creatinine, or ratio may be elevated.Stool rapid antigen testing: may be positive for rotavirus or calicivirus.Stool reverse transcriptase PCR (RT-PCR) or multiple-x PCR: may detect rotavirus, norovirus, astrovirus, or adenovirus.
Viral gastroenteritis in children
Viral gastroenteritis often has upper GI symptoms, including nausea and vomiting. However, it can present with diarrhoea.
Serum electrolytes,urea, creatinine: usually normal; abnormal if severe dehydration is present.FBC: usually normal; elevated WBC count and granulocytes if sepsis is present.Stool microscopy: usually normal; presence of WBCs suggests infection with an invasive cytotoxin-producing organism such as Salmonella, Shigella, or Yersinia enterocolitica.Stool culture: negative.
Crohn's disease
Crohn's disease (CD) is a chronic condition. It produces diffuse abdominal pain, which may be accompanied by mucous, blood, and pus in the stool.Non-bloody intermittent diarrhoea is a common symptom in CD.Up to 20% to 30% of patients with CD may have perianal lesions, including skin tags, fistulae, abscesses, scarring, or sinuses.
Stool culture: negative.Upper GI and small bowel series: oedema and ulceration of the mucosa with luminal narrowing and strictures.CT/MRI abdomen: skip lesions, bowel wall thickening, surrounding inflammation, abscess, fistulae.Colonoscopy: aphthous ulcers, hyperaemia, oedema, cobblestoning, skip lesions.
Ulcerative colitis
Ulcerative colitis is a chronic condition. Abdominal pain severity and location depend on disease severity and extent. It can range from mild crampy pain associated with tenesmus to severe pain with either severe or complicated colitis (i.e., toxic megacolon, perforation).Diarrhoea is usually bloody; severity and frequency are related to disease severity and extent.Patients have gross or occult blood on digital rectal examination.Bleeding severity and frequency is related to disease severity and extent.
Stool culture: negative.Histology: continuous distal disease, mucin depletion, basal plasmacytosis, diffuse mucosal atrophy, absence of granulomata and anal sparing.Colonoscopy: rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas (rarely seen), normal terminal ileum (or mild 'backwash' ileitis in pancolitis).
Acute appendicitis
Abdominal pain of appendicitis may be similar to that of Campylobacter infection. Pain is usually generalised but can be localised to the RLQ.
CT scan showing inflammation of the appendix.
Clostridium difficile-associated diarrhoea
History of recent antibiotic use.
A positive test for C difficile toxin is confirmatory in the correct clinical scenario.Colonoscopy shows pseudomembranes on top on normal mucosa.
Toxin-mediated food poisoning (Staphylococcus aureus, Clostridium perfringens , Bacillus cereus )
Vomiting is more likely, and the incubation time much shorter (4-24 hours) in toxin-mediated food poisoning.
Detection of organism in stool and food source.
Amoebiasis
No fever or systemic features unless extra-intestinal amoebiasis.Weight loss if ongoing.RUQ abdominal pain if related liver abscess.
Stool microscopy for cysts and parasites: positive for Entamoeba.
Cryptosporidiosis
Diarrhoea is found in virtually all cases and may continue for up to 3 weeks or sometimes longer; it may also have a relapsing and remitting nature. Stools tend to be watery and voluminous. In immunocompromised people, the diarrhoea may be chronic and intractable.
Stool microscopy for cysts and parasites: positive for Cryptosporidium oocysts.
Giardiasis
Weight loss if chronic.Frequent flatulence.
Stool microscopy for cysts and parasites: positive for Giardia cysts and trophozoites.
Leishmaniasis
Weight loss in visceral leishmaniasis. Associated hepatosplenomegaly.
Spleen aspirate, bone marrow aspirate, or lymph node fluid; amastigote form of Leishmania species in macrophages or monocytes.
GI arteriovenous malformations (AVM)
AVMs can cause GI bleeding, which is either slow and gradual, or rapid and intermittent. Diarrhoea is less likely.
Direct visualisation of AVM during endoscopy.

Carbon monoxide poisoning

Viral infection
Should be determined from the history whether the nausea, vomiting, diarrhoea may be due to a viral infection such as influenza or food poisoning.
Specific to infectious agent, stool testing if clinically indicated, may help in diagnosis.
Alcohol intoxication
Concurrent CO exposure in intoxicated patients cannot be excluded.
Blood ethanol level.
Sedative hypnotic overdose
Concurrent CO exposure in intoxicated patients cannot be excluded.
Urine toxicological screen specific for the agent. However, this should be interpreted with caution as urine toxicology screens only document a recent exposure and not necessarily toxicity; these tests are often only qualitative and may lead to erroneous assumptions of causation.
Cyanide and hydrogen sulphide poisoning
Rapid onset of symptoms and progression to fatal events is a clinical clue. [14]
Increased levels of serum cyanide and erythrocyte cyanide. Laboratory analysis is non-specific for hydrogen sulphide.
Toluene poisoning
Solvent and aromatic odours, paint on hands and face are clinical clues. [14] Diagnosis of toluene poisoning is a clinical one.
Electrolytes should be measured for associated derangements.

Carcinoid syndrome

Irritable bowel syndrome
Often presents with intermittent and chronic history of diarrhoea.
Urinary 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A will be normal.
Crohn's disease
Right lower quadrant pain and peri-anal lesions. May also present with oral lesions.
Urinary 5-HIAA and chromogranin A will be normal.Inflammatory markers such as C-reactive protein may be elevated in Crohn's disease.Evidence of Crohn's disease on endoscopy.
Menopause
Amenorrhoea or irregular menstrual cycle; vaginal dryness, itching, and dyspareunia; pale, dry vaginal mucosa with decreased rugosity; mood changes.
Urinary 5-HIAA and chromogranin A will be normal. Gonadotropins (LH/FSH) will be elevated.
Asthma
If wheeze is the only symptom of myxoma carcinoid, then it may be mistaken for asthma. Absence of diarrhoea and abdominal pain.
Urinary 5-HIAA and chromogranin A will be normal.

Cardiac tamponade

Constrictive pericarditis
Seen after radiation therapy or after cardiac surgery or recurrent pericarditis.Constrictive pericarditis behaves as if there were a box around the heart. Patients have Kussmaul's sign: an increase in jugular venous pressure with inspiration. This is typically absent in tamponade.
Echocardiogram typically can distinguish between these two as constrictive pericarditis typically has no effusion and a thickened pericardium. Early diastolic filling is rapid, with impaired late diastolic filling in constriction. In tamponade, both early and late filling are impaired.CT or MRI may be used to assess the pericardial thickness.Invasive haemodynamic measurements show a steep y-descent before chamber equalisation that is absent in tamponade, creating a 'dip and platea' or 'square root sign'.
Restrictive cardiomyopathy
Kussmaul's sign.
Differentiated again from tamponade by absence of effusion. Restriction is also marked by LVH, pulmonary HTN, and lack of respiratory reciprocal variation. [25]
Cardiogenic shock
Signs and symptoms similar to advanced tamponade.
Echocardiogram is useful. Expect poor ventricular function or regions of abnormal wall motion. Effusion is rare. No evidence of chamber collapse or reciprocal variation.

Carpal tunnel syndrome

Osteoarthritis (OA)
OA of the first carpometacarpal joint may be associated with CTS, and CTS must be excluded as the two commonly co-exist.Painful, stiff thumb joint, often worse in the evening. Tenderness and crepitus on examination.
Diagnosis is clinical.EMG will be normal (unless CTS co-exists).
Stroke, acute
Often there is sensory and motor loss in a cortical-type pattern (i.e., whole hand or limb, worse distally) or spinal segmental pattern. Ipsilateral face and/or leg may also be affected.
EMG studies show a completely normal peripheral nervous system.MRI or CT scan may show abnormalities in CNS (brain or spinal cord).
C6 radiculopathy
Sudden onset of severe unilateral neck pain radiating to shoulder/arm/scapula. Associated with weakness (mainly shoulder movements and elbow flexion) and numbness predominantly of the dorsal aspect of first and second fingers and lateral aspect of forearm. Decreased or absent biceps and brachioradialis reflexes.
EMG will show normal median nerve studies (including sensory responses to first and second fingers) and lateral antebrachial cut nerve studies.On EMG needle examination there will be denervation in C6 paraspinal muscles and C6 innervated arm/shoulder muscles.MRI of cervical spine will show abnormality such as a herniated disc or osteophyte impinging on the C6 nerve root (CT will be similar except not as sensitive).
C7 radiculopathy
Sudden onset of severe unilateral neck pain radiating to shoulder/arm/scapula. Associated with weakness (mainly elbow, wrist, and finger extensors) and numbness predominantly of dorsal aspect of third finger. Decreased or absent triceps reflex.
EMG will show normal median nerve studies (including sensory responses to third finger).On EMG needle examination there will be denervation in C7 paraspinal muscles and C7 innervated arm/shoulder muscles.MRI of cervical spine will show abnormality such as a herniated disc or osteophyte impinging on the C7 nerve root (CT will be similar except not as sensitive).
Ulnar neuropathy
Sensory symptoms are on the medial aspect of the hand, distal forearm, and fourth and fifth fingers. Abduction of the first dorsal interosseous and fifth abductor digiti minimi is weak. There is no weakness of the thumb. More commonly it is the non-dominant hand that is affected.
EMG will show normal median nerve studies and abnormalities in the ulnar nerve, most probably across the elbow region.
Amyotrophic lateral sclerosis/motor neuron disease
Muscle weakness and atrophy is widespread, progressive, and involves more than just median nerve-innervated muscles. Fasciculations are usually prominent. There may be bulbar symptoms. There should be no sensory and no bowel/bladder complaints.
EMG shows normal sensory nerves. Motor nerve studies and needle EMG shows widespread acute or chronic denervation even in clinically normal muscles and very proximal muscles (e.g., tongue, paraspinals).
De Quervain's tenosynovitis
Pain on movement of thumb and/or wrist; commonly occurs in both wrists and worsens on heavy lifting.Hardening and thickening of the radial styloid may be indicative.
EMG will be normal (unless CTS co-exists). Degenerative or inflammatory joint conditions may be seen on plain x-ray or CT scans.
Lateral epicondylitis
Pain in the lateral elbow and lateral forearm, due to over-use (e.g., tennis). The patient is tender around the lateral epicondyle.May be associated with CTS.
Typically clinical diagnosis; MRI may be confirmatory of extensor carpi radialis brevis degeneration.EMG will be normal (unless CTS co-exists).
Rotator cuff tendonitis
Pain associated with arm movement, especially reaching; pain in shoulder at night.Tenderness on palpation around the shoulder.May be associated with CTS.
MRI may demonstrate inflammation and exclude a tear in the rotator cuff.EMG will be normal (unless CTS co-exists).
Polyneuropathy
Classically patients complain of symmetrical stocking and glove loss of sensation (worse in the feet) with or without mild weakness distally. Distal reflexes are usually reduced or absent.However, there are many forms of polyneuropathy that do not follow this pattern and can present asymmetrically, affecting hands more than feet or motor more than sensory.Polyneuropathy seems to worsen pre-existing entrapment neuropathies (CTS in particular), and so polyneuropathy patients can present purely with CTS symptoms.
EMG shows widespread symmetrical, length-dependent neuropathic changes without focal abnormalities in the median nerve across the wrist segment.Screens for polyneuropathy may show diabetes or excess alcohol use (2 of the most common causes in the developed world).Liver, renal, thyroid, haematological, and metabolic functions are usually also checked, together with vitamin screen (B12 in particular) and protein electrophoresis (myeloma). Depending also on clinical findings, screens for vasculitis, connective tissue disease, and other paraneoplastic conditions may also be obtained.
Brachial plexopathies
Most but by no means all have a history of trauma and are unilateral. Usually easily distinguished from CTS by more widespread motor and sensory symptoms and signs beyond median nerve territory.True neurogenic thoracic outlet syndrome causes weakness in a median nerve territory. The sensory loss, however, is in the medial forearm, hand, and fingers.
EMG shows widespread neuropathy in a truncal, cordal, or mixed pattern.MRI may show increased signal intensity in parts of the plexus and in denervated muscles. The cervical spine and cord is usually normal.
Proximal median neuropathies
Numbness extends across the thenar eminence (palmar branch), and weakness includes forearm pronation (pronator teres) and wrist flexion (flexor carpi radialis). Usually unilateral.
EMG shows neuropathic changes in the palmar branch of the median nerve and in the pronator teres and flexor carpi radialis. There is no focal slowing in the median nerve across the carpal tunnel.
Multiple sclerosis (MS)
In MS the sensory/motor loss may vary over time and place. Distinguishing features, if present, may include optic neuritis, constitutional symptoms, and neurogenic symptoms (bowel/bladder).
EMG studies show a normal peripheral nervous system. MRI or CT scan may show abnormalities in CNS (brain or spinal cord).

Cataracts

Refractive error
Vision improves to normal with a correct spectacle prescription.
Testing of vision with a pinhole will help indicate whether a change in glasses will improve vision without surgery.
Dry eye
May be an abnormal-appearing tear film.
Using a drop of fluorescein and calculating the tear break-up time provides a guide to the degree of stability of the pre-ocular tear film and the likelihood of dry eye. Results with dry eye are likely to be abnormal (<7 seconds).
Glaucoma
Possible decrease in peripheral vision.
Intra-ocular pressure measurement may reveal increased pressure.Visual field testing may reveal field defects.A large cup-to-disc ratio on ophthalmoscopy.
Epiretinal membrane
Distorted or wavy vision.
Fundus examination: evidence of epiretinal membrane or puckering of the macula.
Macular oedema
Blurred or distorted vision.
Fundus examination: evidence of oedema.
Retinal detachment
Flashes of light and numerous little floaters. This may precede a 'curtain' coming over the vision. The patient should be checked for an afferent pupillary defect.
Fundus examination: evidence of tears, vitreous haemorrhage, or detachment.
Optic neuritis
Decreased or patchy vision in one eye, pain on eye movement, or decreased colour vision.Often associated with a diagnosis of multiple sclerosis.
MRI is the most important test to evaluate the optic nerve and to look for any evidence of white matter changes in the brain, especially if the fundus appears normal on physical examination.Defects on visual acuity and colour vision testing.
Vitreous haemorrhage
May be a history of trauma or poorly controlled diabetes mellitus.A sudden decrease in vision or large patchy areas of blurry vision.
Visual acuity reduced on testing.On dilated fundus examination, there may be evidence of blood in the vitreous.
Age-related macular degeneration
Wavy vision or a central area of vision that is blurry.
Fundus examination: may be signs of wet or dry macular degeneration, such as drusen (retinal metabolic by-products that are normally removed) or sub-retinal fluid.
Infectious or inflammatory causes of decrease in visual acuity
Symptoms and signs are specific to each individual diagnosis.A complete examination should be performed to find any possible underlying cause of vision loss.
Fundus examination is required. Other investigations depend on the symptoms and signs detected and the suspected diagnosis.

Cavernous sinus thrombosis

Peri-orbital or orbital cellulitis
Visual symptoms are more prominent in orbital cellulitis because of the involvement of the optic nerve.May manifest in only one eye, whereas cavernous sinus thrombosis (CST) progresses more commonly to both eyes. [43]Less likely to have profound sepsis, meningeal signs and early fixation of the globe compared with CST. [43] [44]
CT scan and MRI of the head can differentiate between early CST and peri-orbital or orbital cellulitis by the presence of enlargement and expansion of the cavernous sinus in CST. [44]If an LP is performed, 75% of people with septic CST will have inflammatory cells on CSF analysis, unlike people with peri-orbital or orbital cellulitis.
Superior orbital fissure syndrome
Presents as ocular pain, proptosis, external ophthalmoplegia (owing to the paralysis of cranial nerves (CNs) III, IV, VI) and neuralgic pain/anaesthesia of the involved areas supplied by the first and second branch of the trigeminal nerve. [45]All differentiating features are subtle and relative.
CT scan or MRI of the head will show involvement of the cavernous sinuses in CST.
Orbital apex syndrome
Presents with internal and external ophthalmoplegia, visual loss and trigeminal nerve (CN V1) anaesthesia. Visual impairment present because of optic nerve involvement. This is less likely to be a feature in CST.Trigeminal nerve anaesthesia is also a differentiating sign.
CT scan or MRI of the head will show involvement of the cavernous sinuses in CST.
Sino-orbital aspergillosis
Presentation similar to the superior orbital fissure syndrome.All differentiating features are subtle and relative.
CT scan or MRI of the head will show involvement of the cavernous sinuses in CST.
Sub-peri-osteal mucocoeles
Presentation similar to the superior orbital fissure syndrome.All differentiating features are subtle and relative.
CT scan or MRI of the head will show involvement of the cavernous sinuses in CST.
Tolosa-Hunt's syndrome
Presents as the superior orbital syndrome.All differentiating features are subtle and relative.Characteristically, responds well to corticosteroids. [46]
Clinical diagnosis may be differentiating.MRI of the head, with and without contrast, is useful in demonstrating inflammatory changes in the superior orbital fissure/orbital apex or the cavernous sinus.
Meningioma
Location can be either spheno-orbital, superior orbital fissure or cavernous sinus.Presenting signs depend on the site of involvement but, generally, this diagnosis results in focal neurological symptoms.There is generally an absence of sepsis, fever and bi-lateral eye involvement.
MRI of the head demonstrating the meningioma as hyper-intense on T1, mixed intensity on T2 and enhancement with gadolinium with a dural tail sign (extension of a mass toward the dura giving the appearance of a tail).
Carotid-cavernous fistula
Usually a history of trauma, especially basilar skull fractures. [47] [48]Can also be caused by rupture of an intra-cavernous carotid aneurysm or an atherosclerotic internal carotid artery and there may be a history of these conditions. [49]Can either be direct with shunts between the cavernous sinus and the internal carotid or as dural shunts between the cavernous sinus and the meningeal branches of the internal or external carotid artery. [49]The direct shunt usually causes pulsatile exophthalmos, in addition to the other symptoms of ophthalmoplegia, a reduced visual acuity and venous congestion. [50]
MRI/magnetic resonance angiography (MRA) or carotid angiography: these tests will demonstrate blockage of the cavernous sinus in CST compared with abnormal connections between the carotid and cavernous sinus in carotid-cavernous fistula.
Rhino-cerebral mucormycosis
Usually occurs in immunocompromised patients, especially people with diabetes, renal failure or neutropenia. [51]Characterised by the presence of black necrotic eschar in the nasal cavity, invasion of bone and blood vessels and earlier exophthalmos. [52]
CT scan or MRI of the head will show significant invasion of bone and blood vessels.There is characteristic hypo-density on T2-weighted MRI. [52]CT scan or MRI of the head will show involvement of the cavernous sinuses in CST.

Cellulitis

Necrotising fasciitis
Initial findings are non-specific and can be similar to those of cellulitis.Marked pain, often out of proportion to the exam, and necrotic bullous change are clinical clues.Crepitus may be present if a mixed anaerobic aetiology is responsible.
Surgical exploration is definitive for diagnosis and a requirement for treatment. This is limb- and potentially life-threatening, and surgical consultation should not be delayed if necrotising fasciitis is suspected. MRI is helpful if the diagnosis is in doubt. [35] [36]MRI: contrast enhancement, thickening of deep fasciae with fluid collection.
Thrombophlebitis, superficial
Tender, palpable cord along affected vein often present.Presence or recent presence of IV catheter or needle also suggests this diagnosis.
Clinical diagnosis.
Deep vein thrombosis
Tenderness of involved vein, history of prior DVT, prolonged immobility, or hypercoagulable state.
Duplex ultrasonography: presence of a thrombus within the vein.
Gout
Suspected in those with history of gout or if area of skin involvement is closely associated with a joint, particularly the first metatarsophalangeal or knee joint.
Presence of urate crystals in joint aspirate.
Lyme disease
Also known as erythema migrans.Residence in or travel to endemic area, history of tick exposure, involvement of sites that are unusual for bacterial cellulitis (e.g., axilla, popliteal fossa, or abdomen) are suggestive. [38]Sometimes has an area of central clearing within the erythema.
Should be differentiated clinically. Serological testing for Borrelia burgdorferi is too insensitive to be useful at this stage. [38]
Dermatitis, contact
Well-demarcated skin involvement, pruritus, and exposure history are suggestive. [34]Often diagnosed on clinical grounds alone.
Biopsy: intra-epidermal spongiosis with monocyte and histiocyte dermal infiltration suggest an allergic contact dermatitis. Irritant dermatitis is characterised by superficial vesicles containing polymorphonuclear leukocytes. [39]
Insect bites and stings
History of insect exposure and pruritus. Often diagnosed on clinical grounds alone.
Biopsy: wedge-shaped dermal mixed inflammatory infiltrate is characteristic. Eosinophils often predominate. [39]
Fixed drug reactions
History of similar reaction with prior exposure to same drug, well-demarcated area of involvement, itching, burning, involvement of lips and/or genitalia.
Clinical diagnosis.
Eosinophilic cellulitis (Wells syndrome)
A short prodrome of itching and burning may precede onset of single or multiple lesions. Recurrence is common and resolution of each episode may occur over weeks. [40]
Histopathology: dermal infiltration with eosinophils and a peripheral eosinophilia can be seen as well. [40]
Sweet syndrome
Well-defined erythematous plaques with a mammillated surface are typical.Fever, malaise, myalgias, and arthalgias are common. [41]
Histopathology: dermal infiltration by polymorphonuclear leukocytes. [41]
Inflammatory carcinoma (carcinoma erysipelatoides)
Involvement of breast, absence of fever.This represents an advanced form of cancer.
Mammography and biopsy should not be delayed.
Relapsing polychondritis
Bilateral involvement, particularly of auricular (pinnae spared) or nasal cartilage, history of similar reaction. [42]
Clinical diagnosis.
Calciphylaxis
Painful, erythematous lesions, often below the knee, with palpable characteristic subcutaneous plaques. Subsequent ulceration may develop. Seen most often in patients with ESRD. [43]
Diagnosis is often made clinically, especially with evolution of lesions. Biopsy is generally avoided due to concern over poor subsequent healing. [43]
Lipodermatosclerosis
Associated with middle-aged women, especially those with venous insufficiency. Seeming predilection for medial leg. [44]
A clinical diagnosis often suffices. Biopsy has been associated with development of chronic ulceration. [44]
Familial Mediterranean fever
A positive family history, recurrent episodes, association with syndrome of fever, serositis, and lower extremity involvement with erysipelas-like lesions are suggestive. [34]
Clinical diagnosis.
Lymphoedema
History of malignancy, previous surgery, radiotherapy, travel to endemic filariasis area, or family history of lymphoedema. Painless unilateral swelling of extremity; non-pitting oedema; skin changes. Positive Stemmer's sign (inability to tent the skin on dorsum of the digits). Symptoms of limb heaviness or weakness.
Lymphoscintigram: dermal backflow, delayed or absent transport, or lack of visualisation of lymph nodes.MRI or CT scan of affected extremity: thickened skin; honeycombing of fluid and fibrous tissue above the muscle fascia.Ultrasound of affected area: thickening of epifascial compartment and skin.Lymphangiography: location of a specific anatomical obstruction.Blood smear for filariasis: presence of microfilariae.

Central airway obstruction

COPD exacerbation
Dyspnoea is not progressive and wheeze is bilateral. Symptoms of dyspnoea, wheeze, and stridor are responsive to pharmacological therapy (e.g., bronchodilators, corticosteroids, antibiotics).
Pulmonary function tests: airflow obstruction with a reduced FEV1 and FEV1 to FVC ratio; lung volumes show different degrees of hyperinflation and air trapping depending on severity; the diffusing capacity of the lung for carbon monoxide (DLCO) may be reduced.CXR: flattened diaphragms and hyperinflation.HRCT chest: areas of lung destruction, consistent with emphysematous change.
Asthma exacerbation
It should be noted that not all conditions associated with wheeze are asthma.Dyspnoea is episodic and not progressive, and wheeze is bilateral. Symptoms of dyspnoea and wheeze are responsive to pharmacological therapy (e.g., bronchodilators, corticosteroids).
Pulmonary function tests: during exacerbations, the FEV1 and FEV1 to FVC ratio will be reduced, the diffusing capacity of the lung for carbon monoxide (DLCO) may be elevated.Bronchodilator reversibility test: shows improvement following administration of bronchodilators.Methacholine challenge: positive.
Pneumonia
Symptoms of pyrexia, rigors, and cough productive of purulent sputum are characteristic.Non-resolving or post-obstructive pneumonia related to CAO will not adequately respond clinically and radiographically to antibiotic therapy, and patients may experience persistent symptoms and CXR signs of infiltrates for >4 to 6 weeks.
CXR: radiologically evident infiltrates that may be unilobar or multilobar.
Vocal cord dysfunction (VCD)
The presentation of VCD may be quite dramatic, often simulating either CAO related to foreign-body aspiration or a severe asthma attack.The clinical scenario and past medical history aid diagnosis.Patients with VCD are often able to complete full sentences and can hold their breath, and the sounds of the attack disappear during a panting manoeuvre. [13] [28]On auscultation, the sounds in VCD are louder over the neck than in the chest.
Pulmonary function tests: the flow-volume loop (FVL) shows a pattern of variable extrathoracic upper airway obstruction, 'sawtoothing' or fluttering on the inspiratory limb which represents fluctuations in the abnormal vocal cord motion may be evident, and the FVL shows significant variability from test to test and may be normal in between attacks. [13]Laryngoscopy: allows direct visualisation of abnormal vocal cord motion. [13]

Central hypothyroidism

Primary hypothyroidism
Absence of symptoms and signs of hypopituitarism such as CNS involvement (headaches, visual disturbances) or pituitary hormone excess (galactorrhoea, acromegaly, Cushing's syndrome).
Low free T4 is observed in both primary and central hypothyroidism.A high TSH would be expected in primary hypothyroidism, whereas in central hypothyroidism TSH is low, normal, or mildly elevated (normal 0.5 to 5.0 mU/L).A high serum antithyroid peroxidase antibody concentration suggests primary hypothyroidism.
Non-thyroidal illness
Abnormal findings on thyroid function tests that occur in the setting of a systemic non-thyroidal illness (NTI) without pre-existing hypothalamic/pituitary dysfunction.The key characteristics are those of the primary disorder.
The most prominent alteration is low serum T3.TSH, T4, and free T4 are also affected in variable degrees based on the severity and duration of the NTI.As the severity of the NTI increases, both serum T3 and T4 levels drop and then gradually normalise as the patient recovers.
Iodine deficiency
Affected patients come from geographical regions where iodine deficiency disorders are endemic.Patients present with goitre, cretinism, and mental retardation.
Occurs when dietary iodine intake is inadequate for thyroid hormone synthesis.TSH levels are increased, and there is an increase in the T3 to T4 ratio.A low 24-hour urine iodine collection <394 nanomol/L (<50 micrograms/L) is consistent with moderate deficiency.
Chronic fatigue syndrome
Patients with both hypothyroidism and chronic fatigue syndrome may experience prolonged fatigue as well as cognitive slowing and memory problems.Symptoms such as cold intolerance, weight gain, weakness, headaches, and visual disturbances suggest central hypothyroidism.Signs such as bradycardia, skin changes, and hair thinning are more consistent with hypothyroidism.
Thyroid hormone levels are normal.
de Quervain's thyroiditis
Symptoms of hypothyroidism are typical in de Quervain's thyroiditis, although most are transient. Local symptoms observed in de Quervain's thyroiditis, such as pain over the thyroid area and dysphagia, are not observed in central hypothyroidism.On physical examination, thyroid tenderness, enlargement, or firmness may be present in de Quervain's thyroiditis, but is not consistent with central hypothyroidism.
TSH is typically elevated in the hypothyroid period of de Quervain's thyroiditis.Serum thyroglobulin and ESR are almost always markedly elevated in de Quervain's thyroiditis, especially in the initial inflammatory phase.
Depression
Slow mentation, fatigue, decreased memory, and somatic complaints are common in both depression and hypothyroidism.Physical examination findings such as dry, coarse skin, periorbital puffiness, bradycardia, and delayed relaxation of deep tendon reflexes are not characteristic of depression.Comorbid psychiatric disorders are more common in those with depression.
Thyroid hormone levels are normal.
Eosinophilia-myalgia syndrome (EMS)
Symptoms common to hypothyroidism and EMS include myalgias, arthralgias, skin changes (thickening of the skin), weakness, and fatigue, as well as difficulty with concentration and memory. [38] [39]A history of acute inflammatory symptoms or prominent pulmonary symptoms suggests EMS.
The presence of blood eosinophilia is essential for the diagnosis of EMS. [38] [39] A polymorphonuclear leukocytosis is also common.Thyroid function tests are normal.
Fibromyalgia
Symptoms common to central hypothyroidism and fibromyalgia include fatigue, depression, myalgias, and headaches (if central hypothyroidism is caused by a mass lesion).A history of generalised pain with specific tender points suggests fibromyalgia.
Thyroid hormone levels are normal.

Central sleep apnoea

Obstructive sleep apnoea (OSA)
Significant snoring, higher BMI, less sleep-maintenance insomnia, crowded oropharynx, and a short and thick neck are suggestive of OSA but can also be seen in CSA.OSA and CSA can and often do co-exist.
Polysomnography shows apnoeas accompanied by significant and paradoxical abdominal and chest wall movements not seen in central apnoeas. [1]
Sleep-related hypoventilation/hypoxaemic syndromes
Occurs in obesity hypoventilation, in patients with a ventilatory control problem, or in patients with a neurological muscular disorder who cannot ventilate appropriately.
ABGs show hypercapnia in sleep-related hypoventilation/hypoxaemic syndromes, unlike CSA where most patient have hypocapnia or eucapnia. [1]Results from chronic hypoventilation and waking hypercapnia.
Depression
Early morning awakening.Overt sleepiness is quite uncommon, and observed breathing patterns (in patients without concurrent sleep-disordered breathing diagnoses) are normal.Morning headaches are unusual.Other symptoms of depression should be present, such as dysphoria, anhedonia, and altered appetite.
Patients with depression most often have abnormal results on standardised depression scales, such as the Beck Depression Inventory or the Patient Health Questionnaire-9.
Paroxysmal nocturnal dyspnoea due to CHF
Orthopnoea often accompanies poorly controlled CHF with paroxysmal nocturnal dyspnoea.
Medical management of CHF should be optimised. If symptom remains, polysomnography may be necessary to determine the cause.
Restless leg syndrome (RLS)
A characteristic history of RLS may be obtained, including an unpleasant sensation in the legs, which almost demand movement (often difficult to describe, but occasionally described as creepy-crawly, cramping, or fidgety sensations), worse in the evening, worse during immobility, and transiently improved by movement of the affected limbs.
RLS is diagnosed by a careful history.Polysomnogram-associated features may include periodic limb movements, but polysomnography is not necessary to make the diagnosis in adults.
Insomnia due to medication effects
Temporal relationship between onset of symptoms and initiation or increase in dose of candidate medications.
Most helpful is a careful review of medications and their adverse-effect profile.If a medication is strongly suspected, improvement in the symptom upon removal of the medication supports this diagnosis. However, this may not always be possible.
Hypersomnia due to inadequate sleep
The sleep history will reveal marked restriction of sleep, such that even patients who are excellent sleepers experience chronic sleep deprivation.
A careful sleep history is often adequate.In more perplexing cases, a sleep diary kept by a spouse or carer, or even actigraphy, which continuously measures gross motor activity, may be required to obtain an accurate assessment of sleep time and pattern.

Cerebral aneurysm

Arteriovenous malformation
Subacute presentation.Presents more often with seizures.
Diagnostic cerebral angiography and/or MRI of the brain will show an arteriovenous malformation.
Hypertensive intra-cerebral haemorrhage
Age >55 years.Hx of hypertension.Headache with focal neurological deficit.
Diagnostic cerebral angiography will be normal.CT or MRI of the brain will show a focal haematoma more typical for a hypertensive haemorrhage.
Cerebral venous sinus thrombosis
Middle-aged woman.Subacute presentation.May have known hypercoagulable state.Papilloedema seen on examination.
Diagnostic cerebral angiography will show slow arteriovenous transit if there is venous hypertension, and a flow defect in a major sinus.Pattern of haemorrhage on CT or MRI will be adjacent to cortical vein or sinus.
Traumatic subarachnoid haemorrhage
Older patient with a fall.Headache usually less severe.
CT or MRI will show haemorrhage focused along the bony contour, sometimes with an associated skull fracture.
Haemorrhagic tumour
Hx of primary malignancy, particularly lung or renal carcinoma.
CT or MRI may show a mass with surrounding haemorrhage.A thrombosed aneurysm may produce surrounding oedema and haemorrhage mimicking a mass.

Cerebral arteriovenous malformation

Cerebral aneurysm
Aneurysmal haemorrhage typically presents with sudden-onset severe headache.
CT head distinguishes subarachnoid blood from intracerebral haemorrhage. However, both cerebral aneurysms and AVMs may cause both types of haemorrhage.MRI and/or angiogram distinguish the underlying pathology.
Cavernous haemangioma
Most frequently present with seizures. haemorrhages tend to be small and their effects depend on their location. They are rarely the source of significant intracerebral haemorrhages.
MRI distinguishes from AVM unless haematoma obliterates the underlying lesion.The 'popcorn' MRI appearance of cavernous malformations is pathognomonic.
Dural arteriovenous fistula
Frequently cause pulsatile tinnitus, and a bruit can often be heard over the fistula. AV fistulas tend to present with symptoms of raised intracranial pressure secondary to increased cerebral venous pressure such as headaches and visual impairment. Haemorrhage is less common.
Direct visualisation of the fistula on MRI and angiogram.
Hypertensive intracerebral haemorrhage
Known hx of hypertension.
Cerebral angiography excludes AVM.
Developmental venous anomaly
No differentiating signs/symptoms.
MRI and cerebral angiography can differentiate this from an AVM.
Intracerebral haemorrhage from drug abuse
Hx of drug use (cocaine, amphetamines, ecstasy) immediately before onset of symptoms.
May or may not be associated with an underlying AVM.Cerebral angiography is recommended to exclude an underlying lesion.
Intracerebral haemorrhage from anticoagulation
Hx of anticoagulant therapy. Excessive cutaneous bruising and ecchymoses may suggest over-anticoagulation. Vascular lesions cannot be completely excluded simply because of hx of anticoagulant therapy.
Coagulation profile should be sought.Cerebral angiography may be required to exclude an underlying AVM (e.g., patients who are over-anticoagulated may still bleed from an unrecognised AVM).
Amyloid angiopathy
Older patients. Hx of cognitive decline or seizures.
No specific tests are available to diagnose amyloid angiopathy, which is usually a diagnosis of exclusion. On CT imaging, lobar haemorrhages with superficial location and cortical involvement, with or without local extension to the subarachnoid and intraventricular spaces, suggest cerebral amyloid angiopathy-related haemorrhage.

Cerebral palsy

Spinal muscular atrophy
Several subtypes. Patient is floppy at birth and exhibits progressive weakness. There is no spasticity, but patients may develop contractures.
DNA testing is available for most subtypes.Muscle biopsy shows changes consistent with denervation, but no fibrosis.Muscle enzymes are normal.Electromyography reveals fascicular degeneration, fibrillation, repetitive discharge, excessive polyphasic potentials, but is not necessary for diagnosis.MRI reveals muscle loss in lower extremities, but is primarily a research tool.
Muscular dystrophy/myopathy
No spasticity, but patients can develop contractures. There are various subtypes, including Duchenne's, Becker's, and limb girdle.Child may be weak at birth or may have apparent normal development until approximately 3 years of age followed by a progressive loss of function and muscle weakness. There may be a positive family history.Examination reveals a positive Gowers' sign with regression of walking ability.Becker's type is less debilitating and manifests later in childhood. Limb girdle type may not present until late teens or 20s.
Muscle biopsy reveals degeneration of cells, reductions in numbers of cells, and inflamed cells. Histochemical testing is possible for specific proteins.Muscle enzymes are elevated.EMG identifies muscle as opposed to nerve disease and nerve conduction studies are normal.DNA testing is available for many but not all subtypes.
Familial/primary dystonia
Onset of muscular deformity occurs after several years of normal development.Presents with sustained periods of muscle contraction and dystonia but without development of contractures. There may be abrupt and violent movements; patients may even sit on their limbs.Positive family history.
Molecular genetic testing is available.
Myelodysplasia
Usually non-spastic. Associated spinal defect and a lack of sensation below a relatively specific spinal segment makes diagnosis obvious.
Ultrasound and x-rays may be used to identify spine/spinal cord defects.
Familial (hereditary) spastic paraparesis
Family history; progressive disease.
Hereditary spastic paraparesis type 4 (SPG4) is the single most common dominantly inherited paraparesis, representing approximately 40% of cases. Genetic consultation may therefore be helpful.
Spinal stenosis/tethered cord
Progressive neurological disease with worsening of the underlying neurology.
MRI of spinal canal reveals the abnormality.
Brain tumour
Initial development can be normal. Presents acutely with headache, raised intracranial pressure, seizures, and focal neurological deficits.Occasionally coexists with cerebral palsy.
MRI reveals a space-occupying lesion.

Cerumen impaction

External otitis
Foul-smelling otorrhoea is present frequently.
Diagnosis is clinical.
Keratosis obturans
Layers of keratin debris lining the circumference of the bony ear canal and often extending onto the tympanic membrane. May cause partial or total ear canal obstruction. After removing the keratin debris the underlying skin of the bony canal often appears red and friable. Keratosis obturans may result in blunting of the angle between the ear canal and the tympanic membrane.
Diagnosis is clinical.
Polyp of ear canal
Signs of infection and purulent otorrhoea. Visualisation of polyp covered by skin or granulation tissue partially or totally occluding the ear canal.
Audiogram usually shows a conductive hearing loss.High-resolution CT scan shows middle-ear and mastoid disease.
Foreign body in ear canal
There may be no differences in signs and symptoms, although there may be a history of foreign-body insertion into the ear canal. Diagnosed by visualisation of a foreign object in the ear canal (e.g., plastic toy, pebble, insect).
Diagnosis is clinical.
Osteoma of ear canal
Visualisation of bony-hard skin covered mass(es) that protrude into the lumen of the ear canal, causing partial or total obstruction of the ear canal.
High-resolution CT scan will demonstrate a mass, but diagnosis is usually made on the basis of the physical exam.

Cervical cancer

HPV infection
No mass; no abnormal bleeding; usually no symptoms.
HPV DNA testing is indicated with an atypical Pap smear (ASCUS - atypical squamous cells of undetermined significance).The term koilocyte refers to the characteristic appearance of HPV-infected cells and is pathognomonic for the presence of HPV. Koilocytosis often remits, but true dysplasia needs further investigation and follow-up.
Pelvic infection
Chlamydia and gonorrhoea are associated with fever, pain, and vaginal discharge, but may be asymptomatic.
Pap smear may be indeterminate due to inflammatory changes. Chlamydia and gonorrhoea testing, wet prep, culture, potassium hydroxide (KOH) testing can identify infection.
Nabothian cyst
Dyspareunia and cystic mass on examination.
Distinguished on clinical examination.
Glandular hyperplasia
May be a finding on Pap smear in an asymptomatic patient.Some patients may have symptoms of heavy, prolonged, frequent, and short or irregular uterine bleeding.
Atypical glandular cells on Pap smear; diagnostic biopsy will distinguish this from cervical cancer.
Mesonephric remnants
Dyspareunia and cystic mass on examination.
Diagnostic biopsy will distinguish this from cervical cancer.
Endometriosis
Pelvic pain, dysmenorrhoea, infertility, dyspareunia, abnormal bleeding, fatigue.
Diagnostic biopsy will distinguish this from cervical cancer.
Cervical polyp
Abnormal bleeding, mass on examination.
Diagnostic biopsy will distinguish this from cervical cancer.
Cervical fibroid
Menorrhagia, painful mass, abnormal discharge, prolapse of the fibroid.
Diagnostic biopsy will distinguish this from cervical cancer.

Cervicitis

Cervical ectropion
Commonly seen in adolescent women, pregnant women, and women on birth-control pills.Usually no history of purulent discharge.Oestrogenic influence on cervical epithelium.
Microscopic examination does not reveal infection or evidence of leukorrhoea.
Cervical dysplasia
Patient may report a history of abnormal Pap smears.
Pap smear: abnormal cervical cytology.Colposcopy: acetowhite epithelium, abnormal vascular patterns (punctations, mosaicism), gross lesion.Cervical biopsy: cervical intraepithelial neoplasia.
Cervical cancer
Patient may report a history of abnormal Pap smears.May present with metrorrhagia (heavy or irregular vaginal bleeding) along with abnormal vaginal discharge.
Pap smear: abnormal cervical cytology.Colposcopy: abnormal vascularity, white change with acetic acid, or obvious exophytic lesions.Cervical biopsy: confirms diagnosis histologically and identifies subtype.
Pelvic inflammatory disease (PID)
Patient presents with abdominal pain and tenderness, pelvic pain and cervical tenderness, fever, nausea/anorexia.Clinical exam of cervical motion tenderness and abdominal tenderness, as well as sign of fever or leukocytosis, can be used to diagnose this condition.Patients with Chlamydia trachomatis cervicitis, if left untreated, carry a 40% risk of developing PID.
Transvaginal ultrasound: classic signs are tubal wall thickness greater than 5 mm, incomplete septae within the tube, fluid in the cul-de-sac, and a cogwheel appearance on the cross-section of the tubal view; may also see tubo-ovarian abscess; may be normal.

Chagas disease

CNS toxoplasmosis
Exposure to cat faeces, consumption of undercooked or raw meat, focal neurological deficit, retinitis.
Serum antitoxoplasma IgM and IgG: detectable with titre.CT/MRI brain: ring-enhancing brain lesion(s), usually multiple, often involving the basal ganglia.
Non-Chagas-related cardiomyopathy
Residence in Chagas non-endemic regions; Hx of infiltrative, storage, toxicity, endomyocardial, inflammatory, endocrine, cardiofacial, and neuro-muscular/neurological causes; nutritional deficiencies; Hx of autoimmune or collagen diseases; Hx of electrolyte imbalance; Hx of cancer therapy.
Differentiating tests vary pending on suspected underlying cause.
Toxic megacolon
Hx of chronic use of drugs that could interfere with neuronal activity. Medication hx of antacids (aluminium hydroxide and calcium carbonate), anticholinergics (pectin), antidiarrhoeals (casein), antiparkinsonians, antidepressives (tricyclics or lithium), antihypertensives or antiarrhythmics (calcium channel blockers), metals (bismuth, iron, or heavy metals), opiates, laxatives, non-steroidal anti-inflammatory drugs, or sympathicomimetics (pseudo-ephedrine).
Microscopy: abnormalities vary depending on suspected underlying cause.
Non-toxic/non-Chagas megacolon
Hx of schistosomiasis, lymphogranuloma venereum, Parkinson's disease, myotonic dystrophy, Fabry's disease (glycolipid accumulation), scleroderma, severe hypothyroidism, or amyloidosis.
Microscopy: abnormalities vary depending on suspected underlying cause.
Typhoid fever
High fever, rose spots (blanching erythematous maculopapular lesions), Hx of travel to the Indian sub-continent.
Serological and microbiological examinations (blood culture, faeces culture, bone marrow culture, urine culture, skin culture): positive for Salmonella typhi.
Visceral leishmaniasis
Hx of travel to Mediterranean basin, Middle East, central Asia, sub-Saharan Africa (in particular, East Africa), northern India, southern Nepal, or northwest Bangladesh; high exposure to sand flies; ulcerative lesions; multiple, non-ulcerative skin nodules; Skin darkening.
FBC: pancytopenia.Microscopic examination of spleen aspiration, bone marrow aspirate, or lymph node fluid: amastigote form of Leishmania species in macrophages or monocytes.
Acute intestinal schistosomiasis (Katayama fever)
Travel to Africa, China, the Philippines, or the Caribbean; haematuria; bloody diarrhoea; genital ulcers.
Parasitological examination of the faeces: visualisation of Schistosoma species eggs.Rectal biopsy: granulomas surrounding eggs.
Infectious mononucleosis
Hx of sexual activity and kissing; tender lymphadenopathy; pharyngitis.
Heterophile antibodies: positive.EBV-specific antibodies: positive VCA-IgM, VCA-IgG, EA, EBNA.
Congenital syphilis infection
Asymptomatic (60% to 90%).Maternal syphilis infection; low birthweight; cutaneous lesions; periostitis; osteochondritis; pseudoparalysis; phinitis; nephrotic syndrome.
Serology (mother and child): VDRL and FTAs positive.
Congenital toxoplasmosis
Mental retardation; blindness; epilepsy.
Serology (mother and child): high toxoplasma-specific IgM and IgG antibody titre.
Hirschsprung's disease
Mainly in young children in first year of life; vomiting; explosive passage of liquid and foul stools; delayed passage of meconium; abdominal distension.
Rectal biopsy: absence of ganglion cells, and presence of an excess of non-myelinated nerves.Contrast enema: contracted distal bowel and dilated proximal bowel, with demonstration of the location of the transition zone in between.
Achalasia
The most common presenting symptoms are dysphagia, regurgitation, and retrosternal pain. These can be slowly progressive over months to years.
Upper GI series shows a typical 'bird's beak' filling defectEsophageal manometry shows incomplete relaxation of the lower esophageal sphincter

Chancroid

Syphilis infection
Ulcers are typically solitary, indurated, and painless.Causes painless inguinal lymphadenopathy, which is usually bilateral.May occur with Haemophilus ducreyi in a mixed infection.More commonly associated with systemic symptoms such as fever and rash. [7] [12]Condyloma latum is accompanied by a rash.
RPR test is positive.RPR test is non-specific and must be confirmed by serology for Treponema pallidum.
HSV infection
Lesions form vesicles.Ulcers are shallower than chancroid lesions with a clean base.Lymphadenopathy is usually bilateral and not fluctuant.May occur with H ducreyi in a mixed infection.More commonly associated with systemic symptoms such as fever, headache, and malaise. [5] [7] [10] [12]
Herpes DNA detected by PCR, positive herpes culture, or positive Tzanck smear of lesion biopsy.View image
Lymphogranuloma venereum
Tender inguinal lymphadenopathy without associated genital ulcerations.Lesions, if present, are painless. [12] [48]
Culture or PCR from bubo aspirate positive for Chlamydia trachomatis.
Granuloma inguinale
Genital ulcers are painless. [12] [15]Lymphadenitis is unusual.
Ulcer scraping or biopsy positive for Klebsiella granulomatis (also known as Calymmatobacterium granulomatis).
Traumatic ulceration
History of trauma is usually present. [12]Unlikely to cause bubo formation.
Diagnosis is clinical.
Squamous cell carcinoma of the skin
No distinguishing characteristics.
PCR, culture, and serology for infections are negative.Biopsy of the lesion provides definitive diagnosis.
Behcet's syndrome
Oral lesions are more common.Systemic symptoms such as fever, arthralgias, uveitis, and abdominal pain are common. [12]
Pathergy test is positive, leading to pustule formation within 48 hours.
Cutaneous drug reaction
Recent history of antibiotic use or chemotherapy. [12]
Skin biopsy is diagnostic.
Crohn's disease
Patients have predominantly peri-anal lesions.More likely to have systemic symptoms, such as fever, diarrhoea, weight loss, and abdominal pain.Inguinal lymphadenopathy is uncommon. [12]
Colonoscopy and biopsy are diagnostic.
Gonorrhoea infection
Not associated with genital ulcers.More commonly associated with systemic symptoms such as fever, rash, and arthritis. [12]
Gram stain-positive for gram-negative diplococci.Culture positive for Neisseria gonorrhoeae.Nucleic acid amplification test positive for N gonorrhoeae. [12] [48]
Urinary tract infections in men
Not associated with genital ulcers or inguinal lymphadenopathy. [12]More likely to have fever and abdominal/flank pain.
Positive urine culture.
Urinary tract infections in women
Not associated with genital ulcers or inguinal lymphadenopathy. [12]More likely to have fever and abdominal/flank pain.
Positive urine culture.

Charcot-Marie-Tooth disease

Diabetic neuropathy
The most common cause of neuropathy, normally seen in adults.
Fasting plasma glucose: ≥7 mmol/L (≥126 mg/dL).Oral glucose tolerance test: 2-hour post-glucose load ≥11.1 mmol/L ( ≥200 mg/dL).Plasma or urine ketones: medium or high quantityHbA1c: >6%.
Chronic inflammatory demyelinating polyneuropathy
Symmetrical polyneuropathy involving both distal and proximal muscles. Usually more rapidly progressive than CMT, with an acute onset.
Sural nerve biopsy: may show inflammation in addition to demyelination.
Acquired peripheral neuropathy
Causes include toxins, hypothyroidism, vitamin deficiencies, and renal failure.As with CMT, deep tendon reflexes are diffusely absent or reduced.Timeline of symptom onset and the past medical history help to differentiate this condition from CMT.
Investigations and results dependent on the underlying cause.Fasting plasma glucose: ≥7 mmol/L (≥126 mg/dL) in diabetes mellitus.Oral glucose tolerance test: 2-hour post-glucose load ≥11.1 mmol/L ( ≥200 mg/dL) in diabetes mellitus.Urea and creatinine: may show chronic renal impairment.Liver function tests: deranged in hepatitis, toxin ingestion.Thyroid function tests: TSH elevated, free T4 and free T3 reduced in hypothyroidism.ESR and CRP: elevated in SLE, mononeuritis multiplex.Serum B12: reduced in vitamin B12 deficiency.
Hereditary spastic paraplegia (HSP)
Spasticity, hyper-reflexia, and Babinski's signs are indicative of an upper motor neuron lesion. CNS manifestations, including upper motor neuron signs, are uncommon in CMT.
Genetic testing: specific gene mutation known to cause HSP.MRI: atrophy of spinal cords, possible atrophy of cerebral cortex.
Spinocerebellar degeneration
Ataxia is a major component of the symptomatology, but some patients have an associated neuropathy.
MRI: spinocerebellar degeneration.

Child abuse

Coagulopathy
Family history of easy bleeding following dental extractions or postoperatively. Other presentations include prolonged epistaxis or bleeding from umbilical cord stump.
FBC, platelet function tests, prothrombin time (PT), prolonged thrombin time, von Willebrand factor and other clotting factor assays help identify the aetiology.
Osteogenesis imperfecta (OI) and other bone fragility disorders
Type I (mild) and type IV (moderate-to-severe) OI: recurrent fractures in infancy and childhood; associated with dentinogenesis (discoloured teeth) and joint laxity. Type 1 has associated blue sclera.Type II (lethal) and type III (severe, progressively deforming) OI: easily diagnosed clinically and radiologically due to the severity.There may be a family history of the disease or of recurrent fractures, deafness, or hernias.
X-ray reveals wormian bones, reduced bone density, and evidence of multiple fractures.Genetic testing is possible in a few centres, but expensive. Genetic testing is only recommended in types II and IV; other types are diagnosed clinically and radiologically. [49]
Dentinogenesis imperfecta
Brown discoloration of teeth, loss of enamel.May be associated with osteogenesis imperfecta.
Can be detected by mutation analysis and/or skin biopsy.
Glutaric aciduria
A metabolic disorder that may be asymptomatic for some time after birth. Symptoms develop during an inter-current illness and are those of lethargy and neurological impairment.Co-existent subdural haemorrhages have been reported.
Organic acid analysis shows marked glutaric aciduria and increased 3-hydroxyglutaric acid.CT scan shows evidence of frontal lobe wasting.Definitive diagnosis is from glutaryl-CoA dehydrogenase analysis in fibroblasts.
Rickets of prematurity
History of prematurity and of prolonged total parenteral nutrition (TPN) and/or diuretics.May be other co-existent disease precipitating rickets.
Bone density with DXA scan, if age-appropriate, confirms this clinical diagnosis. Normal ranges are available for all ages.
Phytophotodermatitis
Appears after skin has been in contact with a psoralen (e.g., from plants such as rue, citrus fruit juices, perfumes, bergamot oil) and then exposed to sunlight.The key is a precise history, as the lesions appear 'spontaneously' and may be mistaken for scalds or bruising.
Diagnosis is clinical.
Impetigo
Lesions are crusting and new lesions keep cropping. In particular, new lesions appear following contact with another area of affected skin (e.g., lesion on the arm touching the trunk).
Skin swabs will confirm the presence of a bacterial pathogen.
Mongolian blue spot
Can occur anywhere on body, most commonly on the buttocks. Found in children of Asian or southern Mediterranean origin.Diagnosis relies on genetic susceptibility of child, presence since birth, absence of tenderness or induration, and no change in colour over succeeding days.
Diagnosis is clinical.
Coining
A traditional remedy used in Southeast Asia, so a history of using traditional remedies is key to the diagnosis.Linear marks, usually found on the back or chest and appearing over the part of the body giving rise to symptoms (e.g., appearing over chest if the child has a cough). They may also be noted in a collapsed child following resuscitative efforts.
Diagnosis is clinical.
Moxibustion
A traditional remedy, so a history of using such remedies is key to the diagnosis.Characteristic multiple, circular, erythematous or superficial burns found around the umbilicus or chest following burning the moxa herb on the skin (although variations may be performed).Marks are found over the part of the body giving rise to symptoms (e.g., the abdomen if the child has abdominal pain/vomiting).
Diagnosis is clinical.
Vitamin K deficiency
May present with widespread CNS, GI, or skin bleeding.History of no vitamin K prophylaxis after birth (particularly in breastfeeding mothers) aids the diagnosis.
Diagnosis is clinical.

Chlamydia pneumoniae infection

Mycoplasma pneumoniae pneumonia
Cannot be differentiated clinically or by routine laboratory tests. Co-infections with M pneumoniae, Chlamydia pneumoniae, and other bacteria are not uncommon. [13] [14]
Demonstration of seroconversion in paired sera, presence of anti-M pneumoniae IgM antibody in children aged 10 or under (several FDA-approved tests are available), demonstration of presence of M pneumoniae by culture and/or PCR.
Pneumonia, bacterial
Patients with pneumococcal pneumonia may be more ill, and are more likely to have comorbidities, but presentations overlap significantly. [13] [14]
Positive culture for Streptococcus pneumoniae or other bacteria in sputum, blood, and/or pleural fluid.
Viral pneumonia
Similar presentation with wheezing present.
Chest x-ray unlikely to show consolidation or pleural effusions.

Cholangiocarcinoma

Hepatocellular carcinoma (HCC)
Patients generally present with symptoms of advancing cirrhosis, with jaundice, ascites, asterixis, pedal oedema, periumbilical collateral veins, and possibly alcoholic stigmata. There may be a history of variceal bleeding and episodes of hepatic encephalopathy.
The same imaging modalities are used.HCC is the more likely diagnosis if the lesion is peripheral and cirrhotic parenchyma is present, but ultimately it will be pathology that distinguishes between the two tumours.
Ampullary carcinoma
Presents with many of the same features as cholangiocarcinoma, with jaundice, pruritus, anorexia, weight loss, and a distended, palpable gallbladder.Patients may have diarrhoea, which is not commonly associated with cholangiocarcinoma.
Diagnosis of ampullary lesion is made using ERCP; however, confirmation of malignancy requires histological examination.
Pancreatic carcinoma
A characteristic feature is significant weight loss. Patients may also experience epigastric or back pain, which is not commonly seen with cholangiocarcinoma.
The same imaging modalities are used. It may be clear from CT or MRI that the tumour is arising from the body of the pancreas, but more difficult to distinguish if the tumour is arising from the head of the pancreas. Ultimately it is the histology that will distinguish between the two tumours.
Choledocholithiasis
Gallstones in the common bile duct (CBD) can present with signs and symptoms of obstructive jaundice. In addition, the presence of gallstones in the CBD and cystic duct obstruction can mimic Courvoisier's sign (presents with enlarged gallbladder, which would be similar to an obstruction secondary to tumour in the bile duct). Gallstones in the gallbladder can cause no symptoms.
ERCP will definitively diagnose and treat this condition.
Cholangitis
This typically presents as a triad of fever, RUQ pain, and jaundice.Although a common cause for the infection can be gallstones in the common bile duct, the infection can also be superimposed upon obstruction caused by a tumour.
Clinical diagnosis of a consequence of biliary obstruction regardless of cause.WBC count is elevated and imaging (CT, MRCP, ERCP) demonstrates biliary obstruction.Blood cultures may be positive for aetiological organism.

Cholecystitis

Acute cholangitis
Classic findings are fever and chills, jaundice, and abdominal pain (Charcot's triad). [37] About 50% to 70% of patients with cholangitis develop all 3 symptoms. [29]
Magnetic resonance cholangiography or MRI findings: intra-ductal purulent material with low signal intensity on heavily T2-weighted images and/or intermediate signal intensity on fat-suppressed T1-weighted images.
Chronic cholecystitis
Repeated bouts of mild attacks or chronic irritation by large gallstones. [2]
No specific investigations.Mucosal atrophy and fibrosis of the gallbladder wall in postoperative specimens.
Peptic ulcer disease
Burning, epigastric pain that occurs hours after meals or with hunger. Often wakes the patient at night. Pain improves with eating.
Endoscopy may reveal a peptic ulcer.
Acute pancreatitis
Epigastric or periumbilical abdominal pain that radiates to the back.Ecchymosis in the periumbilical region (Cullen's sign) or the flank (Grey Turner's sign) may be present in severe pancreatitis.
Tripling of amylase.Pancreatic inflammation on CT abdomen.
Sickle cell crises
Associated with gallstone disease.Pain can occur anywhere in the body (including RUQ), which may be unrelated to gallstone formation.
Blood film may show sickle cells.Haemoglobin electrophoresis shows the presence of haemoglobin S or C.
Appendicitis
Pain is usually located in the right iliac fossa but may start in the periumbilical region.
Abdominal CT scan: dilated appendix with thickened, hyperenhancing wall and mural stratification of appendix.
Right lower lobe pneumonia
Productive cough with fever.Examination may reveal bronchial breath sounds, crepitations, and dullness to percussion.
Right lower lobe consolidation on CXR.
Acute coronary syndrome
Typically central chest pain, squeezing in nature, radiation to jaw or left arm. Pain may be felt in the epigastrium.May be a history of angina and risk factors for CAD (e.g., smoking, hypertension, diabetes mellitus, obesity).
Ischaemic changes on ECG (ST elevation or depression, T-wave inversion, left bundle-branch block).Elevated cardiac enzymes.
GORD
Burning sensation in chest after meals, worse on bending over or lying down. May be acid reflux and dysphagia
Therapeutic trial with proton pump inhibitors (PPIs) leads to symptom relief.Oesophagitis may be seen on endoscopy.pH <4 for >4% of the time is typical.

Cholelithiasis

Gastroparesis
May have hx of diabetes mellitus and previous abdominal surgery that may result in vagal nerve injury. Can present with postprandial nausea, bloating, vomiting, early satiety.
Solid phase gastric emptying study of opiates or other medications which delay gastric emptying: positive.
Peptic ulcer disease (PUD)
May have hx of Helicobacter pylori infection, NSAID use, smoking, increased age, or positive family history of PUD. Presents with burning or gnawing pain in the upper abdomen, particularly with food consumption and often improved with antacids.
EGD: peptic ulcer.H pylori breath/stool test: may be positive if H pylori causative.
Hepatitis A
May have hx of close personal contact with an infected person, men who have sex with men, and exposure to a known food-borne outbreak. Can present with fever, malaise, anorexia, nausea, vomiting, hepatomegaly, clay-coloured stools. Absence of post-prandial pain.
Hepatitis A autoantibodies: positive. IgM: the presence of IgG indicates permanent immunity.
Hepatitis B
May have hx of multiple sexual partners, men who have sex with men, injection drug users. Can present with hepatomegaly, splenomegaly, ascites, spider angiomata. Acute disease may present with fever. Chronic disease may present with palmar erythema. Absence of post-prandial pain.
Hepatitis B autoantibodies: positive.The best test for acute hepatitis B is core Ab IgM. Hepatitis B surface antigen becomes positive several weeks later. The presence of Hepatitis B surface antibody indicates immunity.
Hepatitis C
May have hx of IV drug use and/or blood transfusion. Most patients with acute disease are asymptomatic, but may have fatigue, arthralgia, or jaundice. Chronic disease presents with signs of chronic liver disease (e.g., ascites, spider angiomata). Absence of post-prandial pain.
Hepatitis C autoantibodies: positive in chronic hepatitis C. In acute infection, measurement of RNA is required (i.e., nucleic acid amplification test).
Autoimmune hepatitis
May have hx of genetic predisposition and immune dysregulation. Can present with anorexia, fatigue, hepatomegaly.
LFTs: mild-to-moderately elevated; serum globulin: elevated; serum albumin: reduced; prothrombin time: prolonged.ANA, SMA, anti-SLA/LP, p-ANCA, anti-ssDNA, anti-dsDNA may be positive in type 1 disease. Anti LKM-1, anti-LKM-3, anti-LC1 may be positive in type 2 disease.
Gallbladder cancer
May have hx of ulcerative colitis, liver fluke infection, liver disease, or exposure to thorium dioxide. Can present with painless jaundice and/or weight loss.
CT abdomen: intrahepatic mass lesion, dilated intrahepatic ducts, and/or localised lymphadenopathy may be seen.
Gallbladder polyps
Often found incidentally on imaging for other conditions.
Abdominal ultrasound: polypoid lesion.
Acalculous cholecystitis
Positive Murphy's sign (tenderness suddenly becomes worse during deep inspiration, and produces inspiratory arrest).
Abdominal ultrasound: may produce Murphy's sign.Hepatobiliary iminodiacetic acid (HIDA) scan: gallbladder non-visualisation.
Choledochocyst
Abdominal mass/distention. Usually found incidentally.
MRCP: cyst(s) seen branching off intra- and/or extrahepatic bile ducts or fusiform dilatation of the extrahepatic bile duct.LFTs: abnormal.
Sphincter of Oddi dysfunction (SOD)
Postcholecystectomy biliary pain.
ERCP with biliary manometry: lack of sludge or retained stones.
Non-biliary acute pancreatitis
History is helpful in identifying alcohol use, possible offending medications, or recent biliary tract endoscopy/surgery.
Triglycerides: elevated; usually >11.3 mmol/L (>1000 mg/dL) (can be lower in fasting patients).Calcium: elevated; checking ionised calcium is useful.MRCP/abdominal ultrasound: negative.

Cholera

Other infectious diarrhoea
Many causes of infectious diarrhoea will be impossible to differentiate from cholera, especially in the early stages of disease or mild cases.Bloody diarrhoea is suspicious for Shigella or enterohaemorrhagic Escherichia coli.
Stool culture is the standard, but some techniques (e.g., for Campylobacter) are difficult and not performed in the developing world.PCR for toxins help distinguish enterohaemorrhagic E coli.
Amoebic dysentery
Volume of diarrhoea rarely exceeds 1 litre/hour for adults.Bloody diarrhoea common.
Fresh stool microscopy shows amebae ingesting red blood cells.
Strongyloides
Rare to have large-volume stool loss.
Stool microscopy for eggs and live parasites requires training and good equipment to detect Strongyloides stercoralis.
Giardiasis
Giardiasis often causes offensive, yellow, sulphur-scented stools.Rare to have large-volume stool loss.
Stool microscopy for eggs and live parasites requires training and good equipment to detect Giardia.
VIPoma
Volume of diarrhoea rarely exceeds 1 litre/hour.Chronic history.Much rarer than cholera.
Fasting gut hormone analysis confirms diagnosis.Negative stool culture for cholera.
Tubulovillous adenoma
Volume of diarrhoea rarely exceeds 1 litre/hour.Chronic history of diarrhoea.Much rarer than cholera.
Colonoscopy and biopsy of lesions shows adenoma.Negative stool culture for cholera.
Food poisoning
Volume of diarrhoea rarely exceeds 1 litre/hour.
Stool white blood cell count may help differentiate invasive or inflammatory diarrhoea.Stool culture may help isolate specific pathogens.

Cholestasis of pregnancy

Acute hepatitis
Patients usually appear unwell and present with malaise, RUQ pain, prodromal constitutional symptoms, nausea, and occasional emesis.
Bilirubin >85.5 micromol/L (>5 mg/dL) and transaminases between 500 and 3000 units/L.
HELLP syndrome
Typical signs of pre-eclampsia in most, including hypertension, thrombocytopenia, and proteinuria. Around 20% will not have hypertension; however, thrombocytopenia will distinguish from intrahepatic cholestasis of pregnancy (ICP).
Thrombocytopenia, transaminases 50 to 2000 units/L. Renal impairment may be present.
Acute fatty liver of pregnancy
Patients appear unwell, frequently with malaise, nausea, many with typical signs of pre-eclampsia, coagulopathy, and renal impairment. Hypertension present in >70% of cases.
Transaminases <1000 units/L, hypoglycaemia in most, elevated prothrombin time, elevated creatinine, and proteinuria. CT or MRI of liver showing fatty infiltration. Liver biopsy with fatty infiltration, but rarely needed for diagnosis.
Plaques, urticaria, and papules of pregnancy (PUPPS)
Typically presents with pruritic papules. May be difficult to differentiate clinically as pruritus may result in a rash-like appearance in women with ICP.
Clinical diagnosis.

Cholesteatoma

chronic suppurative otitis media
On otoscopy there is perforation of the pars tensa but no evidence of cholesteatoma.
Diagnosis is clinical.
otitis externa
On otoscopy there is swelling of the external canal and a scant discharge. The tympanic membrane is not visible or, if visible, appears inflamed, but no evidence of cholesteatoma.
Diagnosis is clinical.
benign necrotising otitis externa
The patient reports severe otalgia; a history of diabetes or other immunosuppression.On otoscopy there are granulations in the ear canal but no evidence of cholesteatoma.
CT scan demonstrates soft tissue swelling of the ear canal with or without erosion of the petrous temporal bone.
myringitis
On otoscopy there is inflammation of the tympanic membrane with or without granulations, but no evidence of cholesteatoma.
Diagnosis is clinical.

Chronic atrial fibrillation

Atrial flutter with variable AV conduction
History and physical examination may be similar to AF patients.
ECG tracing to examine all leads for flutter waves: ECG shows more discrete, uniform atrial activity, such as the typical saw tooth pattern described for typical atrial flutter. View image
Multifocal atrial tachycardia
Often seen in severely ill patients with pulmonary disease.
ECG tracing: more than 3 different but distinct P-wave morphologies associated with varying PR intervals and RR intervals. View image
Atrial tachycardia with variable AV conduction
There may be no difference in signs and symptoms.
ECG tracing: discrete regular P waves often different from the sinus P waves. View image
Sinus rhythm with premature atrial contractions or with premature ventricular contractions
There may be no difference in signs and symptoms.
ECG tracing: sinus with premature atrial View image or ventricular complexes. View image

Chronic congestive heart failure

Ageing/physical inactivity
Ageing, deconditioning, and/or obesity may cause a reduction in effort tolerance due to dyspnoea and/or fatigue, but without the additional major and minor criteria for diagnosing heart failure.
Elucidation of the precise reason for exercise intolerance can be difficult because several disorders may co-exist in the same patient. Echocardiography in heart failure shows characteristic signs of heart failure. However, a clear distinction can sometimes be made only by measurements of gas exchange or blood oxygen saturation or by invasive haemodynamic measurements during graded levels of exercise (i.e., cardiopulmonary exercise test with VO2max).
COPD/pulmonary fibrosis
Dyspnoea may be episodic, with or without environmental triggers, and is usually accompanied by cough, wheezing, sputum, and a history of smoking or industrial exposure.
Pulmonary function tests will give definite diagnosis of an obstructive pulmonary disease. Plasma B-type natriuretic peptide (BNP) levels may be intermediate (100 to 400 nanograms/L or 100 to 400 picograms/mL) in COPD.
Pneumonia
Patients may present with fever, cough, and productive sputum, with focal signs of consolidation (increased vocal fremitus and bronchial breathing).
CXR may show signs of consolidation. FBC may show elevated WBC, and blood cultures may be positive for aetiological organism.
Pulmonary embolism (PE)
Sudden onset of chest pain, dyspnoea, and haemoptysis, especially after childbirth, [82] are suggestive of PE.
ECG is abnormal in the majority of patients with PE and may show a deep S wave in lead I and a deep Q wave and T-wave inversion in lead III (S1-Q3-T3). Other common changes include sinus tachycardia, complete or incomplete right bundle-branch block (RBBB), and T-wave inversion in the inferior (II, III, aVF) or the anterior leads (V1 to V4).Normal levels of D-dimers can help to exclude PE, but raised levels occur in many types of cardiomyopathies as well as in PE.
Post-partum cardiomyopathy (PPCM)
Patients most commonly present with dyspnoea, but other frequent complaints include cough, orthopnoea, paroxysmal nocturnal dyspnoea, haemoptysis, and chest discomfort, which are also common symptoms of pulmonary embolism. [82] PPCM is defined on the basis of 4 criteria: 1) development of cardiac failure in the last month of pregnancy or within 5 months of delivery; 2) absence of an identifiable cause for the cardiac failure; 3) absence of recognisable heart disease before the last month of pregnancy; 4) left ventricular systolic dysfunction shown on echocardiograph. A number of potential risk factors may point to the diagnosis of PPCM, including age >30 years, multiparity, women of African descent, pregnancy with multiple fetuses, a history of pre-eclampsia/eclampsia/post-partum hypertension, and maternal cocaine misuse.
In the presence of raised D-dimers (commonplace in pregnancy) and positive risk factors for thromboembolic events, echocardiography will identify the underlying left ventricular systolic dysfunction and point to the diagnosis of PPCM. It usually shows left ventricular enlargement and significant global reduction in ejection fraction. Other findings may include left atrial enlargement, mitral and tricuspid regurgitation, and a small pericardial effusion.
Cirrhosis
Typically causes jaundice, fatigue, nausea, peripheral oedema, ascites, bruising and prolonged bleeding, gynaecomastia, and haematemesis.
LFTs are abnormal. Ultrasound or CT scan may detect ascites and liver abnormalities. Liver biopsy shows characteristic cirrhotic changes and may reveal the underlying cause.
Nephrotic syndrome
Typically causes peripheral oedema, fatigue, dyspnoea, and loss of appetite.
Urinalysis shows proteinuria, and serum albumin is reduced. Twenty-four-hour urine collection shows >3.5 g protein. Serum urea and creatinine clearance may be abnormal in later stages. Serum cholesterol and triglyceride levels may be raised. Kidney ultrasound and biopsy may reveal the underlying cause.
Pericardial disease
May present with chest pain, typically worse on lying down, swallowing or coughing; tachycardia; dyspnoea; cough; oedema; fatigue; and low-grade fever. Pericardial friction rub may be heard at the left sternal border or apex.
ECG may show electrical alternans or ST elevation and T wave flattening or inversion. Echocardiography may detect pericardial effusion, tamponade, and pericardial fibrosis. CT scan or MRI may show thickened pericardium. Pericardial biopsy may reveal underlying cause.
Venous stasis
Oedema affects lower limbs only, and varicose veins may be present. Skin over the lower legs may be darkened, with ulceration.
Doppler examination may detect incompetent valves in varicose veins.
Deep venous thrombosis
Typically causes pain, swelling, and tenderness of one calf, which becomes red and warm.
D-dimer test may be positive. Ultrasound scan or contrast venography may detect an area of thrombosis.

Chronic fatigue syndrome

Lyme disease
Acute presentation of 'bull's eye' rash.
Clinical observation of rash; exposure to endemic Lyme areas.Positive enzyme-linked immunosorbent assay (ELISA) and Western blot test.
Infectious mononucleosis
Fever; enlarged spleen and/or liver. Waxing and waning symptoms. Periods of symptom remission suggestive of dormant EBV.
Positive for Paul-Bunnell's heterophile antibody testing.Positive EBV-specific antibodies.Atypical lymphocytes; elevated WBC count.Positive reaction to monospot test.
Hypothyroidism
Cold sensitivity; brittle fingernails/hair.
Thyroid stimulating hormone is raised.
Major depressive disorder
Feelings of sadness, hopelessness, helplessness, and/or worthlessness. Thoughts of suicide.
Diagnosis is clinical.

Chronic granulomatous disease

leukocyte adhesion deficiency type I
Classically, patients present in infancy with delayed separation of the umbilical cord, serious recurrent bacterial illness (typically of mucosa and skin), no pus formation, and poor wound healing. [1]
Flow cytometric analysis of neutrophils shows a lack of CD18 expression.
glucose-6-phosphate dehydrogenase deficiency
May present with infections similar to CGD, yet have a history of haemolytic anaemia triggered by fava beans or certain medications. [1]
Genetic testing identifies glucose-6-phosphate dehydrogenase deficiency. [1]
myeloperoxidase deficiency
Typically only associated with concurrent diabetes; these patients tend to have infections with Candida spp. [1] [37]
CGD is excluded based on a normal DHR test.Of note, complete absence of myeloperoxidase activity can lead to decreased DHR histogram shift within neutrophils. [38]Lack of myeloperoxidase can be documented by direct staining of neutrophil intracellular myeloperoxidase and analysis by flow cytometry. [38]
rac2 deficiency
Occurs in a young child with recurrent life-threatening infections associated with leukocytosis and poor pus formation in tissues.Another prominent feature is delayed umbilical cord separation.
There is currently no clinically available diagnostic testing available.
Crohn's disease
Patients may display GI bleeding, prolonged diarrhoea with abdominal pain, fistulae between the GI, GU, and vaginal walls, and perianal skin tags.
Colonoscopy with biopsy shows focal ulcerations, inflammation, sparing of the rectum, fistulae, and perianal disease.

Chronic inflammatory demyelinating polyradiculoneuropathy

Guillain-Barre syndrome (GBS)
GBS typically progresses for <4 weeks. In cases that progress for 4 to 8 weeks, distinction can be difficult, because these cases tend to behave more like CIDP than GBS. [6] [7]Some subacute presentations of CIDP can be monophasic as in GBS. [8] [9]More frequent antecedent infection, respiratory failure, cranial nerve involvement, and autonomic dysfunction. [1] [2] [3] [4] [5]
Demyelinating features on nerve conduction studies tend to be less severe. [48]CSF abnormalities are less common and CSF protein is often not elevated. [1] [2]
Hereditary motor and sensory neuropathy (HMSN)
Early age of onset, slow progression of weakness, skeletal deformities (e.g., pes cavus), and extremely distal weakness. [62]
Electrodiagnostic features include uniform slowing of conduction velocities and the absence of conduction block. [63]Terminal latency index, the modified F ratio, and dispersion of the compound muscle action potential (CMAP) amplitude may also differentiate. [64] [65]Nerve biopsy more often shows areas of abnormally thickened or folded (tamaculous) myelin or areas of hypomyelination in HMSN. [66]
Anti-myelin-associated glycoprotein (anti-MAG) neuropathy
Patients tend to be older, more often male, have a more indolent course, and have only distal weakness. [67] [68]
Conduction block rarely occurs. [68]Electrodiagnostic finding of prolonged distal latencies out of proportion to slowed conduction velocities is a hallmark. [69]The presence of anti-MAG antibodies by ELISA and Western blot is seen in essentially all patients. [70] [71]Widely spaced myelin is the classic pathological finding. [68]Patients do not respond to corticosteroids, intravenous immunoglobulin, or plasma exchange, [72] [68] [73] but recent studies suggest that patients may respond to rituximab. [74]
Monoclonal gammopathy of unknown significance (MGUS)-associated neuropathy
Patients with CIDP and MGUS (usually IgA or IgG) tend to be older and have more distal weakness, a more indolent course, and more sensory involvement. [11] [32] [33]IgA/IgG MGUS without CIDP has a better response to plasma exchange compared with IgM MGUS.
Serum and urine immunofixation will detect the monoclonal protein. [11] [32] [33]Patients often respond less well to immunotherapy. [75]If immunoglobulin level is >15 g/L (>1.5 g/dL), check for a haematological malignancy. [76]
Multifocal motor neuropathy (MMN)
Distal asymmetrical weakness and the lack of sensory signs or symptoms are seen. [77]
Electrodiagnostic studies show multifocal conduction block as the major demyelinating feature. [77] Sensory nerve conduction studies are normal.Anti-GM1 antibodies are found in 50% to 80% of patients.Does not respond to corticosteroids or plasma exchange.
Neuropathy associated with lymphoproliferative disorders
Neuropathy associated with multiple myeloma, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, osteosclerotic myeloma, Waldenstrom's hypergammaglobulinaemia, and Castleman's disease tends to be predominantly distal. [78] [79] Neuropathy associated with cryoglobulinaemia and lymphoma can be multifocal. [80]
Serum and urine immunofixation, quantitative immunoglobulin levels, skeletal survey, and bone marrow biopsy will usually find the haematological abnormality. [76]Nerve biopsy may be needed in lymphoma. [80]Electrodiagnostic studies may have features of axonal degeneration and demyelination, although axonal degeneration may predominate. [78] [79] [80]
Diabetic neuropathies
Typical neuropathy is distal and sensory more than motor. [81]Proximal diabetic neuropathies are often asymmetrical.Progressive weakness is not rapid. [81] [82]
Electrodiagnostic studies show primarily axon loss in diabetes, but secondary demyelinating features can be present. [81] [29] [83] [82]
Vasculitic neuropathy
May mimic multifocal CIDP (Lewis-Sumner variant). [17]
Electrodiagnostic studies show axon loss, although pseudoconduction block can be seen with early lesions. [84]Repeat nerve conduction studies show features typical of axon loss.Nerve biopsy may be needed to document evidence of nerve inflammation.
Drug-induced neuropathy
Look for onset of disease in relation to onset of drug use.Weakness tends to be predominantly distal. [85] [86]
Nerve biopsy may show perineural or Schwann cell lysosomal inclusions with amiodarone and perhexilene. [85] [86]
Mitochondrial disorders (MNGIE syndrome)
Neuropathy is predominantly distal.Look for associated features: gastrointestinal neuropathy, ophthalmoplegia, cachexia, hearing loss, or leukoencephalopathy. [87]
Muscle biopsy shows mitochondrial pathology due to multiple mitochondrial deletions (cytochrome oxidase negative fibres and ragged red fibres).Laboratory tests show serum lactic acidosis and markedly elevated serum thymidine levels. [87]
Leukodystrophies
In metachromatic leukodystrophy and Krabbe's leukodystrophy, the presenting features may be of a polyneuropathy indistinguishable from CIDP. [88]In adrenoleukodystrophy, CNS signs and symptoms predominate.
Electrodiagnostic findings are more uniform in the leukodystrophies. [88]Brain MRI findings are prominent and nerve biopsy usually shows Schwann cell inclusions in leukodystrophies.
Infection-associated neuropathy
Look for signs and symptoms of infection (e.g., HIV, hepatitis, Lyme disease).
HIV test, hepatitis serology, or Lyme serology may be positive.CSF pleocytosis with >10 cells/mm^3. [30] [31]
Systemic lupus erythematosus
Mononeuropathy multiplex or distal symmetric polyneuropathy in 10% to 25% of patients. [26] [27] [28]
ANA, anti-dsDNA, and anti-Sm tests are positive.Complement levels may be low.Nerve biopsy may show evidence of vasculitis. [26] [27] [28]
Sarcoidosis
Cranial neuropathy is most common.Acute or subacute multifocal sensory motor neuropathies are rare. [26] [27] [28]
Sarcoid granulomas are rarely found in nerve biopsies.Endoneurial or epineurial inflammatory infiltrates may be present. [26] [27] [28]
Thyroid disease
Neuropathy with hypothyroidism or hyperthyroidism is predominantly distal and sensory, and usually improves with correction of thyroid status. [3] [40] [42]
Thyroid function studies. [3] [40] [42]
Amyloidosis
Typically, presentations include distal axonal sensory neuropathy, small-fibre neuropathy, carpal tunnel syndrome, or autonomic neuropathy. Rare presentations of multifocal neuropathy with demyelinating features have been reported. [89] [90]
Amyloid present on nerve biopsy. [91]Electrodiagnostic studies may have features of axonal degeneration and demyelination, although axonal degeneration may predominate. [91] [89] [90]Transthyretin mutation analysis for familial amyloidosis. [90]

Chronic lymphocytic leukaemia

Leukaemic phase of mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma
No differentiating features.
Mantle cell lymphoma, follicular lymphoma and lymphoplasmacytic leukaemia cells may mimic CLL morphologically.CLL cells are positive for CD5 and CD19 on flow cytometry.Mantle cell lymphoma is negative for CD23 and positive for cyclin D1, whereas CLL cells are positive for CD23 and negative for cyclin D1.
Small lymphocytic leukaemia (SLL)
SLL is essentially the same disease as CLL: it presents with lymphadenopathy but without lymphocytosis in peripheral blood.
Morphologic and immunophenotypic features of a lymph node of SLL are identical to CLL.

Chronic myelogenous leukaemia

Leukemoid reaction
There are no specific clinical differentiating features.
High WBC count resolves once underlying condition is treated.
Benign neutrophilic leukocytosis
There are no specific clinical differentiating features.
Fluorescent in situ hybridisation (FISH): negative for BCR-ABL fusion gene.
Atypical CML
There are no specific clinical differentiating features.
FISH: negative for BCR-ABL fusion gene.
Chronic myelomonocytic leukaemia
There are no specific clinical differentiating features.
Bone marrow examination: dysplastic changes in the myeloid lineage.Peripheral blood smear: wide range of immature granulocytes and monocytosis.FISH: negative for the BCR-ABL fusion gene. May be positive for PDG-FR beta fusion gene. [13]
Essential thrombocytosis
More indolent clinical course.Unlikely to transform into acute leukaemias.
Bone marrow examination: megakaryocytic hyperplasia.FISH: negative for BCR-ABL, positive for JAK2 mutation. [14]FBC: high platelet count.
Ph+ acute lymphoblastic leukaemia
Much more rapid disease course.Patients often present with anaemia and thrombocytopenia. B symptoms are common (e.g., fever, night sweats, and weight loss).
Peripheral blood smear-blasts.Bone marrow examination and flow cytometry should show predominance of immature B lymphocytes.FISH: positive for 190-kDa BCR-ABL fusion. [1]

Chronic pain syndromes

Paraneoplastic syndrome
Primary or secondary tumours in bone, joints, involving nerves, tendons, the head and neck, major organs or soft tissues present with constitutional symptoms and proximal muscle pain. Paraneoplastic syndrome symptoms usually do not respond to analgesia or corticosteroid treatment. A thorough tumour work-up should be performed in patients who are unresponsive to first-line chronic pain treatment, as removal of the tumour may lead to a resolution of symptoms.The Lambert-Eaton syndrome, a paraneoplastic condition associated with small-cell lung cancer, may cause proximal muscle weakness. Cancer may also result in neural impingement, causing radiculopathy or myelopathy.
Tumour screening includes routine baseline tests including CXR, FBC, chemistry panel and urinalysis. Age-appropriate cancer screening tests should also be performed (i.e., fecal occult blood testing, colonoscopy, mammogram). Additional specialised testing should be directed by the history, examination findings and abnormalities found on the routine CXR and laboratory tests. Sagittal MRI effectively identifies multi-level metastatic spinal disease. Other specific tests as directed by clinical evaluation.
Hypothyroidism
May show signs of muscle and joint pain, weakness in the extremities and fatigue; however, delayed relaxation of deep tendon reflexes is strongly suggestive of hypothyroidism.May mimic chronic pain syndromes, particularly fibromyalgia, which is often associated with change in weight and depression.
An elevated TSH, elevated T3 and T4, and elevated CK helps to differentiate hypothyroidism.
Polymyalgia rheumatica (PMR)
Presents with history of neck, shoulder girdle and/or hip girdle stiffness and pain, occurring in patients more than 50 years of age, commonly female. Patients complain of difficulty rising from seated or prone positions, varying degrees of muscle tenderness, shoulder/hip bursitis and/or oligoarthritis. Rapid improvement is almost invariable within 24 to 48 hours with low-dose prednisolone. Fifteen percent to 20% of patients with PMR have giant cell arteritis (GCA); 40% to 60% of GCA patients have PMR.
Diagnosis of PMR is made via history and with supportive laboratory tests indicating an elevated ESR or C-reactive protein.
Giant cell arteritis (GCA)
New-onset unilateral headache, jaw claudication associated with chewing tough foods, diffuse mandibular discomfort, dental discomfort, sinus pain and pressure, and/or tongue pain are associated with GCA. Blindness, diplopia or blurry vision and an abnormally thickened, tender, erythematous or nodular temporal artery are also found. Patients more than 50 years old with new-onset headache should be screened for GCA or temporal arteritis. Fifteen percent to 20% of patients with PMR have GCA; 40% to 60% of GCA patients have PMR.
Elevated ESR or C-reactive protein. A positive temporal artery biopsy showing a granulomatous vasculitis confirms the diagnosis of GCA. Diagnostic and therapeutic corticosteroid trial.
Polymyositis
Symmetrical weakness of shoulder and pelvic girdles.
Elevated muscle enzyme levels (e.g., CK) often with a positive ANA titre.Characteristic changes in EMG associated with polymyositis include increased needle insertional activity, spontaneous fibrillations, low-amplitude short-duration polyphasic motor potentials and complex repetitive discharges.Diagnosis is confirmed with muscle biopsy, indicating immune cell infiltration and destruction of muscle fibres.
Depression
Depression is diagnosed clinically with a finding of more than 5 of the following symptoms, present during the same 2-week period: depressed mood, anhedonia, weight changes, libido changes, sleep disturbance, psychomotor problems, low energy, excessive guilt, poor concentration and suicidal ideation. Depression may be associated with degrees of anxiety disorder, which may be associated with muscular tension.
No differentiating tests.
Analgesic overuse
Clinical diagnosis may require medicine-use diaries and prescription refill records to identify overuse of medicines. Headache or pain pattern reassessed 1 month after analgesics discontinued or drug taper completed. Analgesic overuse may be associated with bilateral, constant headaches lasting 8 to 24 hours in patients taking analgesics, triptans, opioids, barbiturates or ergotamines.
No differentiating tests.

Chronic pancreatitis

Pancreatic cancer
A change in the severity of pain, fear of food (due to pain), weight loss, and jaundice may occur.
CT and endoscopic retrograde cholangiopancreatography (ERCP) may detect a pancreatic mass or duct stricture. [106]Other differentiating tests include biopsy and elevated blood tumour markers (CA19-9, CEA).Exclusion of malignancy frequently requires surgical resection to ensure a reliable histopathological examination.
Acute pancreatitis
Symptoms of mild acute pancreatitis are similar to chronic pancreatitis.Distinguishing features of severe acute pancreatitis include evidence of persistent organ failure (respiratory insufficiency, renal insufficiency, hypotension, and altered mentation).
Three-fold or more elevation in serum amylase and/or lipase.Abdominal CT shows interstitial or necrotising pancreatitis.
Biliary colic
RUQ pain, nausea, vomiting, and anorexia, which is exacerbated by eating fatty foods.The duration of pain is shorter (1 to 2 hours) than in chronic pancreatitis.
Abdominal ultrasound may show cholelithiasis, and the diagnosis can be confirmed by cholescintigraphy.Elevated liver enzymes and common bile duct dilation occur with choledocholithiasis and biliary strictures.
Peptic ulcer disease
Distinguishing features include upper abdominal discomfort, nausea, belching, bloating, iron-deficiency anaemia, and possibly melaena and haematemesis.
OGD or upper GI series will demonstrate ulceration.Empirical trial of appropriate management, such as proton-pump inhibitor, resulting in symptomatic improvement would help to differentiate from chronic pancreatitis.
Mesenteric ischaemia
Peri-umbilical, post-prandial abdominal pain, fear of food (due to pain), and weight loss with a soft abdomen suggest chronic mesenteric insufficiency.Acute mesenteric ischaemia typically presents with acute onset of severe peri-umbilical pain.
Acute and chronic mesenteric insufficiency can be diagnosed by clinical suspicion and angiography. Diagnosis requires clinical suspicion because serum elevation in lipase and amylase can occur in this setting and lead to an erroneous diagnosis of pancreatitis.
Aneurysm, abdominal aorta
Usually asymptomatic until rupture or dissection, when the patient will present with abdominal or back pain, a pulsatile abdominal mass, and hypotension.
Typically diagnosed incidentally with abdominal ultrasound, CT scan, or MRI.
MI
Inferior wall MI may present with epigastric pain, nausea, vomiting, diaphoresis, and dyspnoea.
Diagnosed by ECG, cardiac enzymes.
Intestinal obstruction
Typical symptoms include a crescendo-decrescendo pattern of abdominal pain accompanied by nausea and vomiting.
Diagnosed by abdominal x-rays and/or CT imaging studies. Diagnosis requires clinical suspicion because serum elevation in lipase and amylase can occur in this setting and lead possibly to an erroneous diagnosis of pancreatitis.
Irritable bowel syndrome
Common condition that presents with abdominal pain and altered bowel habit.
Clinical diagnosis.
Gastroparesis
A motility disorder characterised by nausea, vomiting, early satiety, and weight loss. Common aetiologies include diabetes mellitus, post-viral, scleroderma, and medicines (e.g., opiates).
Diagnosed by gastric emptying study with or without manometry.
Somatisation disorders
Occur in patients with neuropsychiatric disease who describe pain and GI, sexual, and neurological symptoms.
Clinical diagnosis.
Radiculopathy
Pain is constant and/or precipitated by positional changes, such as torsion of spine and leg lifts, and may be reproducible with palpation of chest wall and spine.Unilateral abdominal pain localises to a dermatome distribution, possibly wrapping around or radiating to the back.
Diagnosed using spine imaging studies and EMG.
Post-herpetic neuralgia
Pain may be persistent after the disappearance of shingles. Typically a burning pain with altered sensation.Examination may show evidence of skin erythema or vesicles localising to a dermatome.
Clinical diagnosis.
Abdominal wall pain
Consider focal abdominal wall nerve impingement if there are scars, abdominal wall hernia, or abdominal wall haematoma.
Investigate with abdominal wall ultrasound or CT to exclude abdominal wall hernia and rectus sheath haematoma. Nerve impingement responds typically to trigger point injection.
Nephrolithiasis
May present with unilateral pain localising or radiating to a linear distribution from the groin/testicle to the abdomen and back.Associated symptoms may include nausea, vomiting, dysuria, urinary urgency, and haematuria.
Non-contrast helical CT scan detects renal collecting system opacities.Additional imaging methods include ultrasonography, abdominal x-ray, and intravenous pyelogram.Urinalysis detects microscopic haematuria.

Chronic pelvic pain

Endometriosis
Cyclical pain in early endometriosis, progressing to continuous pain. Diagnosed based on the presence of endometrial glands and stroma outside of the uterine cavity.
Laparoscopy and biopsy: endometrial glands and stroma.
Adenomyosis
Initially cyclic pain, typically beginning after pregnancy. Requires pathological examination of the excised uterus for definitive diagnosis.
Ultrasound may be suggestive; definitively diagnosed on pathological examination of removed uterus.
Pelvic adhesions
Suggested by a history of previous surgery or infection with tenderness on manipulation of the uterus or adnexa.
Diagnosed at laparoscopy..
Chronic pelvic inflammatory disease (PID)
Suggested by a history of previous infection or multiple sexual partners with tenderness on manipulation of the uterus or adnexa.
Diagnosed at laparoscopy.
Interstitial cystitis
Elevated bladder pain or the presence of irritative voiding symptoms.
Suggested by questionnaire and a response to alkalinised lidocaine instillation; definitively diagnosed at cystoscopy with hydrodistension.
Vulvodynia
Pain with insertion at intercourse.
Diagnosed by physical examination. Tenderness limited to areas of the vestibule only.
Levator ani syndrome (pelvic floor tension myalgia)
Only a portion of the levator muscle may be generating pain.
Diagnosed by physical examination.
Haemorrhagic ovarian cysts
Typically causes severe, acute pain but may evolve into chronic pain. Will frequently resolve with time. Persistent, larger (>3 cm) cysts may need to be excised.
Ultrasound.
Irritable bowel syndrome
Requires at least two of three major criteria and as many minor criteria as possible to secure the diagnosis.
Rome III criteria; no specific diagnostic test.Irritable bowel syndrome management is based on symptom control and typically includes hydration and stool bulking or softening agents. If diarrhoea or constipation predominate, targeted medical management of either can be done but may have significant side effects. Consultation with a gastroenterologist interested in irritable bowel syndrome is recommended.
Fibromyalgia
Tenderness to palpation of individual muscles. In pelvic pain, these typically include the lower, lateral borders of the rectus sheath.
Diagnosed by physical examination.

Chronic pyelonephritis

Acute pyelonephritis
Acute infections may be superimposed on underlying chronic pyelonephritis.Presents with anorexia; fevers or chills; nausea and vomiting; constant, usually dull, back pain; and haematuria.
The blood leukocyte count may be elevated.Urinalysis should show leukocytes and blood, and urine cultures will be positive.
Renal calculi
Renal stones usually cause intermittent, sharp, often radiating pain.
Spiral CT scan of the abdomen is the test of choice.Ultrasound of the kidneys may also demonstrate renal or bladder calculi but may miss ureteral calculi due to overlying gas in the intestines.
Renal cancer
There are no differentiating symptoms or signs.
Difficult to differentiate xanthogranulomatous pyelonephritis from renal cancer on imaging; diagnosis often not made until following nephrectomy. [28] [30]

Chronic renal failure

Diabetic nephropathy
History of poorly controlled DM for 5 to 10 years. Often with co-existing diabetic retinopathy.
HbA1c is typically >7%.Diagnostic tests include urinalysis for microalbumin or protein and a serum creatinine for GFR assessment.The quantification of proteinuria is variable over time and will decrease as the GFR declines.Urine microalbumin is helpful to confirm the diagnosis of early diabetic nephropathy prior to the onset of macroalbuminuria.Kidney ultrasound will typically show small, atrophic kidneys only in late stages of the disease, once substantial renal injury occurs.
Hypertensive nephrosclerosis
History of poorly controlled hypertension for years. More common in black people than white people.
Diagnostic tests include urinalysis for microalbumin or protein and a serum creatinine for GFR assessment.The urine sediment is described as bland without formed elements or haematuria. Quantification of proteinuria is <2 g/24 hours.Kidney ultrasound typically reveals small, atrophic kidneys.
Ischaemic nephropathy
History of long-standing essential hypertension that is suddenly uncontrolled. More common in white people and older people.Often will have a history of atherosclerotic disease such as CAD or PVD. There is also a history of tobacco abuse and hyperlipidaemia.
The urine sediment is described as bland, without formed elements or haematuria. Quantification of proteinuria is <2 g/24 hours.Kidney ultrasound reveals asymmetrical kidney size of ≥2.5 cm with unilateral disease, and duplex scan demonstrates an increase in the resistive index, suggesting obstruction.Angiotensin-converting enzyme (ACE) inhibitor renogram, CT angiogram, magnetic resonance angiogram, or renal arteriogram (test of choice) demonstrates luminal narrowing of the renal artery.
Obstructive uropathy
More common in men and older people. Often due to prostatic enlargement or cancer.Typical symptoms include urinary frequency, hesitancy, inability to empty the bladder completely, and decrease in urinary stream.UTIs may develop.Rectal examination may reveal prostatic enlargement or nodules.
Kidney ultrasound is the diagnostic test of choice to document kidney obstruction. It would show hydronephrosis, and there may also be post-void residual volume in those cases when there is obstruction to bladder outflow.
Nephrotic syndrome
Often associated with a more sudden onset of hypertension, or acceleration of essential hypertension and development of periorbital and peripheral oedema.
Laboratory evidence may reveal hyperlipidaemia and an increase in serum creatinine, and urinalysis has proteinuria as defined at >3.5 g/24 hours.A kidney biopsy is required to determine the pathological lesion for nephrotic syndrome.Serological tests for secondary causes of nephrotic syndrome such as ANA in SLE, HIV in focal segmental glomerulosclerosis, and hepatitis B and C in membranous nephropathy, and serum protein electrophoresis for amyloidosis, are often helpful in confirming the diagnosis of the nephrotic syndrome.
Glomerulonephritis
Often associated with a sudden onset of hypertension or acceleration of essential hypertension.Patients with autoimmune disorders may have a skin rash or arthritis; post-infectious glomerulonephritis has a recent history of a pharyngeal or cutaneous infection; bloody diarrhoea is associated with haemolytic uraemic syndrome.
Laboratory evidence reveals an increased serum creatinine, and urinalysis is significant for haematuria and proteinuria.Urine sediment is evaluated for the presence of dysmorphic RBCs and RBC casts, which are diagnostic of glomerulonephritis.Serological tests such as ANA, complement levels, hepatitis B and C antibodies, anti-neutrophil cytoplasmic antibody, anti-glomerular basement antibody, and anti-streptolysin O titre are often helpful in confirming the diagnosis of glomerulonephritis.A kidney biopsy is required to confirm the pathological lesion of the glomerulonephritis.

Chronic sinusitis

Acute sinusitis
No symptoms or signs reliably differentiate acute from chronic sinusitis. Both present in a similar fashion, although symptoms are generally less pronounced in chronic sinusitis. The distinction between the 2 is based upon the duration of symptoms (<4 weeks versus >12 weeks, respectively). Fatigue may be more common in chronic sinusitis, whereas fever and acute toxicity are associated with acute (bacterial) sinusitis.
No differentiating tests.
Allergic rhinitis
Clear rhinorrhoea, itching, sneezing, ocular irritation, and seasonality of symptoms suggest a predominant allergic component.
Scratch and intradermal tests show a positive reaction (oedema, erythema, wheal, and flare to positive allergens; RAST [blood] tests positive to allergens).
Allergic fungal sinusitis
Similar symptoms; often unilateral.
CT scan shows hyperdensities within opacified sinuses. MRI has classic appearance of dropped signal on T2-weighted images. Operative findings include thick 'peanut butter'-consistency mucus, while histology demonstrates non-invasive fungal elements and Charcot-Leyden crystals.
Sinonasal tumours (benign and malignant)
Can occur in the sinuses, nasal cavity, or nasopharynx. Treatment for chronic sinusitis usually fails; symptoms are often unilateral and refractory. Constitutional symptoms may be present.
CT/MRI may show invasion or destruction of nearby structures that is suspicious for malignancy. Biopsy/tissue histology may reveal malignant cells. Histology differs widely according to multitude of benign and malignant neoplasms.
Turbinate hypertrophy
Predominant complaint is nasal obstruction, which often improves with topical nasal decongestion. Associated with allergy or nasal irritation.
Anterior rhinoscopy may show inflamed, swollen (hypertrophic) turbinates that respond to topical decongestion.
Foreign bodies
Common in children. Symptoms may be unilateral with specific onset.
Foreign bodies can be seen on anterior rhinoscopy, endoscopy, and imaging studies (e.g., CT). Associated mucosal inflammation and purulence may be seen.
Juvenile nasopharyngeal angiofibroma
Invariably occurs in adolescent boys, who present with nasal obstruction (often unilateral) with frequent nosebleeds.
Nasal endoscopy shows vascular-appearing nasopharyngeal mass. CT and MRI will show mass centred in area of sphenopalatine foramen; often extending medially into nasal cavity/nasopharynx and laterally to involve pterygopalatine fossa and possibly infratemporal fossa.
Migraine
Symptoms unique to migraine include photophobia, aura, unilateral pain (often throbbing), and visual disturbances. Some patients will not have the classic migraine symptoms but instead a mid-facial pain variant. Most patients presenting with primary complaint of headache or facial pain will fall into this category.
A normal sinus CT scan and unremarkable endoscopy serve as objective evidence against a sinonasal cause for headache. A trial of a triptan can be diagnostic for migraine as a cause for headache or facial pain.

Chronic spinal cord injury

Non-compressive myelopathy
Similar neurological picture. No history of trauma or other acute event.
MRI confirms the lack of spinal cord compression or trauma.
Transverse myelitis
Signs of a unilateral involvement, incomplete lesion, or a Brown-Sequard's type of lesion.
Lumbar puncture demonstrates increased WBC count and absence of infection.Spinal cord MRI reveals a cord lesion that enhances after gadolinium administration.

Chronic venous insufficiency

Diabetic foot ulcer
Hx of diabetes. Foot wounds occur in the presence of peripheral neuropathy secondary to repetitive stress.Ulcers form on the plantar aspect of the foot or on the dorsal aspect of the digits from repetitive moderate stress.
In the presence of concomitant diabetes and neuropathy, wound location is often the defining factor.Fasting plasma glucose ≥7 mmol/L (≥126 mg/dL) is diagnostic of diabetes.
Arterial ulcer
Hx of peripheral arterial disease.Ulcers secondary to arterial insufficiency are located on the distal margins of the foot and are frequently gangrenous or 'punched out' in appearance.
Non-invasive vascular studies may help to exclude peripheral arterial disease, although wounds of mixed aetiology are not uncommon.A Doppler-derived ankle-brachial index <0.92 is abnormal. If foot pulses are absent or diminished, the ankle-brachial index is <0.8 and the patient has foot or leg ulcers.More detailed arterial imaging such as duplex arterial ultrasound can be performed to document the level and degree of arterial obstruction.
Squamous cell carcinoma (Marjolin)
Longstanding non-healing wound with irregular edges.
Skin biopsy is diagnostic of squamous cell carcinoma.
Pyoderma gangrenosum
Wound may increase in size and inflammation after surgical debridement.
Skin biopsy is diagnostic of pyoderma gangrenosum.
Kaposi's sarcoma
Hx of immunosuppression (e.g., HIV infection, organ transplantation, immunosuppressive therapies).Raised purplish lesions that may be confused with venous lesions.
Skin biopsy is diagnostic of Kaposi's sarcoma.
Lymphoedema
Usually unilateral.Characterised by a dorsal foot buffalo hump and loss of the web spaces between the toes (Stemmer's sign).
Duplex ultrasound is normal or minimally abnormal.
Congestive heart failure
Hx of dyspnoea (on minimal exertion, orthopnoea, paroxysmal nocturnal dyspnoea) and weight gain.Bilateral pitting oedema with blebs and bullae in severe cases. Ulceration is rare.
Chest x-ray: cardiomegaly, bilateral lower lobe shadowing, pleural effusion, enlarged hilar vessels, upper lobe diversion, fluid in horizontal fissure, Kerley B lines.Echocardiogram: systolic and diastolic dysfunction, evidence of underlying cause.
Renal disease
Bilateral oedema. Ulceration is rare.
Serum electrolytes: elevated potassium.Serum urea and creatinine: elevated.Urinalysis: possible haematuria and proteinuria.
Hepatic disease
Bilateral oedema. Ulceration is rare.
Liver function tests: results depend on underlying cause.

Churg-Strauss syndrome

Wegener's granulomatosis
Absence of asthma or eosinophilia. Peripheral neuropathy is more common in CSS.
FBC with differential will typically show no eosinophilia in Wegener's granulomatosis.Pulmonary function testing will typically be normal in Wegener's granulomatosis or may show evidence of extrathoracic airway obstruction in cases of subglottic stenosis. Alveolar haemorrhage and glomerulonephritis are relatively rare in Churg-Strauss syndrome (CSS) but common in Wegener's granulomatosis.
Microscopic polyangiitis
Absence of asthma. Peripheral neuropathy is more common in CSS.
FBC with differential will typically show no eosinophilia in microscopic polyangiitis.Pulmonary function testing will typically be normal in microscopic polyangiitis.Alveolar haemorrhage and glomerulonephritis are relatively rare in Churg-Strauss syndrome, but common in microscopic polyangiitis.
Hypereosinophilic syndrome
Absence of asthma or of clinical vasculitis such as palpable purpura, petechiae.
Flow cytometry of peripheral blood may be abnormal. Molecular testing for the FIP1L1/PDGFR alpha mutation may be positive in hypereosinophilic syndrome (HES). Renal failure is more common in Churg-Strauss syndrome.
Parasitic disorders
Absence of asthma or of clinical vasculitis such as palpable purpura, petechiae.
Stool studies are positive in helminthic infections. Renal failure is uncommon in parasitic disorders.
Allergic bronchopulmonary aspergillosis
Absence of clinical vasculitis such as palpable purpura, petechiae.
The presence of skin test reactivity to Aspergillus antigens or serum antibodies to Aspergillus fumigatus. Renal failure is uncommon in allergic bronchopulmonary aspergillosis.
Chronic eosinophilic pneumonia
Absence of clinical vasculitis such as palpable purpura, petechiae.Typically occurs in women and non-smokers. May be seen in women undergoing radiotherapy for breast cancer.
Bronchoalveolar lavage with >40% eosinophils is suggestive of eosinophilic pneumonia. Biopsy differentiates from Churg-Strauss syndrome (CSS). Presence of vasculitis is seen in CSS in addition to presence of eosinophils. Chest x-ray shows a pattern termed a photographic negative picture of pulmonary oedema. Renal failure is more common with CSS.

Cirrhosis

Constrictive pericarditis
Raised jugular venous pressure, tachycardia, and atrial fibrillation.Heart sounds: quiet, third heart sound (ventricular knock) present.
ECG: tachycardia, atrial fibrillation, low-voltage QRS complexes, T-wave abnormalities.Doppler ultrasound: ventricular filling abnormalities.
Budd-Chiari syndrome
Abdominal pain, diarrhoea, and progressively worsening ascites.
Doppler ultrasound and abdominal CT: absence of hepatic vein filling.Abdominal CT: rapid contrast clearing of caudate lobe.
Portal vein thrombosis
Signs and symptoms of the underlying cause such as acute pancreatitis (severe upper abdominal pain radiating through to the back, vomiting, absent bowel sounds, pyrexia, hypovolaemic shock, skin discoloration paraumbilically [Cullen's sign] and in the flanks [Grey Turner's sign]), ascending cholangitis (pyrexia, malaise, rigors, right upper quadrant pain, jaundice, dark urine, and pale stools), or abdominal sepsis (pyrexia, abdominal pain, signs of peritonism).
Magnetic resonance (indirect) or direct angiography: normal hepatic venous pressure gradient (measure of portal pressure).Doppler ultrasound and abdominal CT: portal vein filling defect, absence of flow in the portal vein.
Splenic vein thrombosis
Signs and symptoms of pancreatitis: severe upper abdominal pain radiating through to the back, vomiting, absent bowel sounds, pyrexia, hypovolaemic shock, and skin discoloration paraumbilically (Cullen's sign) and in the flanks (Grey Turner's sign) in acute pancreatitis; non-specific abdominal pain exacerbated by eating, diarrhoea, steatorrhoea, weight loss, and mild pyrexia in chronic pancreatitis.
Abdominal ultrasound and CT: evidence of splenic vein thrombosis.Magnetic resonance (indirect) or direct angiography: normal hepatic venous pressure gradient (measure of portal pressure).
Inferior vena cava (IVC) obstruction
Signs and symptoms of renal cell carcinoma: classic triad of haematuria, flank pain, and flank/abdominal mass with weight loss and HTN.
Abdominal ultrasound and CT: evidence of IVC obstruction.
Schistosomiasis
History of travel to endemic areas.Constitutional symptoms of febrile illness: malaise, rigors, sweating, weight loss, anorexia, vomiting, diarrhoea, headache, muscular aches and weakness, and abdominal pain.Signs of febrile illness: urticarial rash, pyrexia, and lymphadenopathy.
Magnetic resonance (indirect) or direct angiography: normal hepatic venous pressure gradient (measure of portal pressure).
Sarcoidosis
Lung involvement: dry cough and dyspnoea.Skin involvement: altered pigmentation (hypo- or hyperpigmented); maculopapular skin lesions on face, back, and extremities; and erythema nodosum on legs.Eye involvement: anterior or posterior uveitis, dry eyes (sicca), and glaucoma.
CXR findings are dependant on the stage of disease progression: hilar lymphadenopathy, diffuse reticulonodular shadowing (parenchymal disease), and upper lobe fibrosis.Liver biopsy: non-necrotising/caseating granulomas.
Nodular regenerative hyperplasia
No differentiating signs and symptoms.
Liver biopsy: small regenerative nodules with minimal or no fibrosis on reticulin staining.
Idiopathic portal HTN (hepatoportal sclerosis)
No differentiating signs and symptoms.
Liver biopsy: no evidence of cirrhosis.
Vitamin A intoxication, arsenic, and vinyl chloride toxicity
No differentiating signs and symptoms.
History generally reveals exposure.

Clostridium difficile-associated disease

Antibiotic-associated diarrhoea (AAD)
AAD includes osmotic diarrhoea associated with antibiotic use. Nausea and diarrhoea present. Absence of fever.
All tests within normal limits. Negative tests for C. difficile toxin.
Ischaemic colitis
History of stroke, hypotension, heart failure, diabetes, or abdominal radiation exposure. Symptoms of bloody diarrhoea, abdominal pain, vomiting, and fever.
Colonoscopy reveals inflamed mucosal surface or ischaemic ulcers. Angiography reveals arterial flow disruption.
Bacterial or viral gastroenteritis
History of travel, eating contaminated food, or family members also ill. Stool and blood bacterial culture tests warranted. May have history of bloody stools.
Blood as well as stool culture positive for invasive bacterial infection.
Inflammatory bowel disease
Chronic diarrhoea that may be bloody with extra-intestinal manifestation.
Colonoscopic and pathological findings suggestive of inflammatory bowel disease.

Cluster headache

Trigeminal neuralgia
Paroxysmal attacks of brief, unilateral, electric-shock-like pains, lasting from a fraction of a second to 2 minutes, usually affecting the second and third divisions of the trigeminal nerve. Trigger factors for pain include shaving, smoking, talking, and brushing teeth. Attacks are stereotyped in the individual patient. No clinically evident neurological lesion. Pain often evokes spasms of facial muscles on the affected side (tic douloureux). [1]
There are no distinguishing diagnostic tests.
Paroxysmal hemicrania
Signs and symptoms are similar, with severe unilateral orbital, supraorbital, or temporal pain and ipsilateral autonomic symptoms of the eye and nose. Attacks are 3 times more common in women than in men; shorter (2 minutes to 30 minutes) and more frequent (between 1 and 40 a day) than cluster headache; and respond to indomethacin. Attacks can be episodic or chronic. [1]
There are no distinguishing diagnostic tests.
Short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
At least 20 attacks of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain lasting 5 seconds to 4 minutes, accompanied by ipsilateral lacrimation and/conjunctival injection. Attacks occur from 3 to 200 times daily. [1]
There are no distinguishing diagnostic tests.
Angle-closure glaucoma
Severe pain in the region of the eye due to raised intraocular pressure. Other symptoms include nausea, blurred vision, corneal oedema, and redness of the eye. [1]
Tonometry shows raised intraocular pressure.Gonioscopy shows narrow angles.Eye examination shows reduced visual acuity; a semi-dilated, fixed pupil; a cloudy cornea; and optic disc changes.
Hemicrania continua
Continuous unilateral headache that lasts for at least 3 months and responds to indomethacin. Headache is of moderate intensity with exacerbations of severe pain. One ipsilateral autonomic feature is usually included. [1]
There are no distinguishing diagnostic tests.
Cluster-tic syndrome
Symptoms of both cluster headache and trigeminal neuralgia. Both conditions need to be treated. [1]
There are no distinguishing diagnostic tests.
Idiopathic stabbing headache
Single or repeated transient stabs of pain felt mainly in the orbit, temple, and parietal area, lasting up to a few seconds and recurring up to many times per day. Location of pain can move around and change sides. More common in people with migraine or cluster headache. [1]
There are no distinguishing diagnostic tests.
Benign cough headache
Sudden onset of headache caused only by coughing or straining, lasts from 1 second to 30 minutes. Usually bilateral. Indomethacin is often effective treatment. Patients often have underlying vascular disease, such as cerebral aneurysms of Arnold-Chiari malformation type 1. [1]
There are no distinguishing diagnostic tests.
Benign exertional headache
Pulsating headache lasts from 5 minutes to 48 hours; brought on only by physical exertion, especially at high altitude or in hot weather. Indomethacin is usually effective. [1]
There are no distinguishing diagnostic tests.
Headache associated with sexual activity
Dull ache in head or neck occurring during sexual activity and intensifying at orgasm, or a sudden, explosive headache occurring at orgasm, lasting up to 3 hours. [1]
There are no distinguishing diagnostic tests.
Hypnic headache
Dull headache occurs only during sleep and wakes the patient. Headache occurs >15 times per month, lasts ≥15 minutes, with no autonomic phenomena. Pain is usually bilateral, is mild to moderate, and can be treated with caffeine or lithium. [1] Onset is after age 50 years.
There are no distinguishing diagnostic tests.
Primary thunderclap headache
Sudden onset of severe headache lasting 1 hour to 10 days and not recurring regularly over the subsequent weeks or months. Often associated with vascular disorders, which must be excluded (particularly subarachnoid haemorrhage). [1]
There are no distinguishing diagnostic tests.
Subarachnoid haemorrhage
Sudden onset of intense and incapacitating headache, often unilateral at onset and accompanied by nausea, vomiting, altered consciousness, and nuchal rigidity. [1]
MRI or CT scan without contrast has >90% sensitivity in the first 24 hours. Lumbar puncture should be performed if neuroimaging has not provided the diagnosis.
Temporal arteritis
Pain and tenderness over temporal artery, which might occur with amaurosis fugax and loss of vision. Pain resolves within 3 days of high-dose corticosteroid treatment. [1]
Duplex scanning of temporal arteries might reveal thickening of the arterial wall. Sedimentation rate is <100 mm/hour. C-reactive protein is usually raised. Biopsy shows giant cell arteritis.

Cocaine abuse

Thyrotoxicosis
Weight loss may be prominent. May be suggestive findings on physical examination of the thyroid, such as tenderness to palpation, goitre, and thyroid bruit.
Elevated T4, suppressed TSH.
Methamphetamine abuse
Reported history of methamphetamine use. Significant dental erosion and skin ulcerations/other skin lesions from scratching and picking may be present.
Urine toxicology screening positive for methamphetamine. [21]
Amphetamine abuse
Medical and psychiatric adverse effects may be longer-lived (days to weeks) than those due to cocaine (typically lasting hours to 2-3 days) due to longer half-life of amphetamines versus cocaine.
Urine toxicology screening positive for amphetamine. [21]
Ephedrine abuse
Reported history of ephedrine use. Significant weight loss may be evident. Alternatively, there may be evidence of particular attention to physique/ muscle development.
Urine toxicology screening positive for ephedrine. [22]
Severe anxiety/panic attack
History positive for similar states unrelated to episodes of cocaine use.
Urine toxicology screening positive or negative.
Psychotic/paranoid disorder
History positive for similar states unrelated to episodes of cocaine use.
Urine toxicology screening positive or negative.
Phaeochromocytoma
This rare tumour secretes catecholamines and can produce many of the symptoms of cocaine overdose, but unaccompanied by mood change.
CT of the abdomen may reveal mass.Urinary catecholamines elevated. [14]

Cocaine overdose

Non-cocaine sympathomimetic overdose
Difficult to distinguish clinically from cocaine poisoning, but the management is similar.The onset of effects is slower and the duration of action longer, especially when ingested orally.Dysrhythmias due to sodium channel effects do not occur. [9]
Cocaine urine assay is negative.Urine immunoassay may identify presence of phencyclidine or amfetamines.Gas chromatography-mass spectrometry can identify many individual sympathomimetics.
Alcohol, sedative or hypnotic withdrawal
Social history may elicit the diagnosis.Alcohol withdrawal becomes more severe as time passes, whereas cocaine-poisoned patients improve as drug is metabolised.
The CAGE questionnaire [18] or Michigan Alcoholism Screening Test (MAST) [19] may be helpful in identifying alcohol dependence.A conscious patient with an ethanol concentration >21.7 or 43.4 mmol/L (>100 or 200 mg/dL) suggests tolerance, but does not establish the diagnosis.
Anticholinergic syndrome
Anticholinergic toxicity can present with tachycardia, hyperthermia, mydriasis, and agitation.Skin is dry, not diaphoretic; bowel sounds are decreased or absent; and urinary retention is present.Treatment is similar to that of cocaine overdose.
Urine drug screen will detect the anticholinergic drug.
Thyroid storm
A history of hyperthyroidism suggests the diagnosis.The onset of symptoms is much more insidious and the duration is much longer.Hypertension is less frequently seen.
Thyroid studies suggest the diagnosis (elevated triiodothyronine, thyroxine, free T4, decreased TSH).
Phaeochromocytoma
Extremely rare.Usually associated with history of hypertension and attacks are usually accompanied by a headache.Symptoms are longer lasting and recurrent.
Fractionated plasma metanephrine is 97% sensitive and 85% specific for phaeochromocytoma. [20]
Infection
History of exposure to cocaine is absent and a history of infection is usually present.
Symptoms respond to empiric treatment of the infection (e.g. antibiotics).Chest x-ray, urinalysis, or lumbar puncture may reveal the source and cause of the infection.
Hypoglycaemia
Cannnot be clinically distinguished from cocaine overdose as autonomic (adrenergic) features overlap.
Bedside serum glucose is diagnostic.

Coccidioidomycosis

Tuberculosis
Symptoms, signs of tuberculosis and of coccidioidomycosis may be similar. For patients with suspected tuberculosis, no residence in or travel to endemic area for coccidioidomycosis is needed for diagnosis.Tuberculosis has an indolent onset and symptoms are unremitting until proper treatment is begun.
Mycobacterial culture of sputum or other sites of clinical involvement will yield positive culture for Mycobacterium tuberculosis.Chest x-ray may show chronic infiltrate, fibrosis, cavities, and retraction, often upper lobe.
Non-tuberculous pulmonary mycobacterial infections
No residence in or travel to endemic area for coccidioidomycosis needed for diagnosis.Onset of symptoms may be acute, but often indolent.
Mycobacterial culture of sputum or other sites of clinical involvement will yield positive culture.
Histoplasmosis
Residence in or travel to an area endemic for histoplasmosis (Mississippi and Ohio river valleys).Fifty percent to 90% of patients have self-limited or asymptomatic pulmonary infection not requiring treatment. [23] Other symptoms include dry cough, chest pain, sweating, fever, and weight loss.
Fungal culture will grow Histoplasma capsulatum.Biopsy shows characteristic organism with fungal stains.Histoplasma urine and serum antigen positivity.Histoplasma antibody assays may be positive. [23]
Blastomycosis
Residence in or travel to an area endemic for blastomycosis (southeastern and south-central states, especially bordering on the Mississippi or Ohio rivers). [24]Symptoms include cough, fever, night sweats, weight loss, chest pain, and dyspnoea.
Culture of sputum or bronchoalveolar lavage fluid.Histopathology of biopsied specimens. [24]

Coccygodynia

Lumbar spondylosis/disc herniation
Pain is relieved by sitting.Pain and/or tenderness may involve the sacrum or lumbar spine, without specific tenderness of the coccyx.No pain or tenderness on palpation of coccyx or rectal examination.
Injection of corticosteroid around the dorsal surface of the coccyx does not relieve pain, indicating pain is referred.MRI of lumbosacral spine may reveal the site of degenerative disc disease or disc herniation.
Proctalgia fugax
Episodic sudden, severe pain in the anal canal that lasts only seconds or minutes. May awaken the patient from sleep. [5]No coccygeal tenderness and rectal examination negative. [5]
Dynamic lateral sacrococcygeal x-ray may be normal and show neither the sacrococcygeal hypermobility (>20° on sitting) nor subluxation.
Levator ani syndrome
Also known as puborectal syndrome, levator spasm, or pelvic floor myalgia.This category may include some cases of idiopathic coccygodynia. [22]Dull ache or pressure sensation in the rectum, exacerbated by prolonged sitting or supine position, which may last hours to days.Tenderness of puborectalis muscle on rectal examination. [5]
Anorectal manometry may show increased pressure; however, this test is controversial.Although some studies have shown increased anal canal pressure and correlated pain relief with a decrease in pressure, other authors have discouraged its routine use, citing unreliability in its diagnostic and predictive value. [5]
Alcock's canal syndrome
Also known as pudendal canal syndrome or pudendal nerve entrapment.Unilateral or bilateral burning, prickling, stabbing, or numbness in the perineum, external genitalia, or scrotum.Pain is worse with sitting and there is a sense of a foreign object in the urethra, rectum, or vagina. [5]
Diagnosis is essentially clinical.MRI reveals normal anatomy, or intercurrent disease unrelated to the diagnosis, or occasionally may reveal a nerve sheath tumour.Pudendal nerve motor latency studies (nerve conduction studies) are usually normal, as sensory fibres are affected preferentially.Diagnostic nerve block, consisting of anaesthetic infiltration within the pudendal canal, results in pain relief for the duration of anaesthesia, but may be technique dependent. [23]
Descending perineum syndrome
Incomplete emptying of stool as rectal wall mucosa prolapses into anal canal, followed by dull aching in perineum and rectum.Anus may protrude with straining.Weak pelvic floor on rectal examination. [24]
Digital rectal examination reveals weak pelvic floor and lack of coccygeal tenderness. Inspection reveals the anus descending below the level of the coccyx.
Pyriformis syndrome
May coexist with coccygodynia. [11]Buttock pain radiating down posterior thigh that may be worse with sitting, exercise, and bending at the waist.Can provoke by internal rotation of flexed thigh (Freiberg's manoeuvre).
MRI rules out lumbosacral pathology as evidenced by degenerative disc disease and/or disc herniation, or, less commonly, tumour or Tarlov cyst.Magnetic resonance neurography may reveal increased signal in proximal sciatic nerve. [25]
Anogenital syndrome
A descriptive diagnosis involving irritating and painful symptoms in the genitourinary, perineal, and anal areas.Perineal or prostatic pain with suprapubic pain and tenderness is present.Irritation of the anal sphincter inhibits voiding.
Diagnosis is clinical and based on history and physical examination. Digital rectal examination may reveal exquisite prostatic tenderness.
Perianal abscess and/or fistula
Perianal abscess may present as erythema, fullness, or fluctuancy near the anus, or a mass on digital rectal examination. Fever, chills, and perianal pain present.A fistula presents as a small opening adjacent to the anus.
Contrast CT or MRI of the sacrum and pelvis will reveal an abscess cavity and/or fistula tract.WBC, CRP, and ESR may be elevated.
Rectal tumours or teratomas
Rare cause of coccygodynia.May present with blood or mucus in the stool, painful defecation, diarrhoea, or straining.Direct extension to the sacrum and coccyx may cause local pain and tenderness.Digital rectal examination reveals a mass.Teratomas are seen in younger age groups.
Contrast CT or MRI reveals a mass in the retrorectal space or pelvic cavity with or without involvement of the sacrum and coccyx.
Tarlov cyst
Rare cause of coccygodynia.Sacral perineural cysts may rarely present with coccygeal pain.May be accompanied by urinary disturbance and pain in the groin region.
MRI of the sacrum reveals nerve root cysts of CSF density, bright on T2 weighted sequences.CT may reveal enlargement of the sacral foramina or thinning of the sacral lamina around the cyst.May or may not fill on contrast myelography.No relief of pain on coccygeal injection with corticosteroid.
Pilonidal cyst
Cyst develops along the dorsal surface of the coccyx near the gluteal fold.Usually contains hair and debris.Localised pain, redness, or pus drainage from a sinus tract. May be asymptomatic.May be caused by excessive sitting.Direct trauma can result in cyst inflammation and exacerbation of symptoms.Typically affects young men aged 15 to 24 years.
Diagnosis is based on history and examination.

Coeliac disease

Peptic duodenitis
Patients present with chronic or recurrent abdominal pain or discomfort centred in the upper abdomen that is commonly related to eating. There may be a history of non-steroidal anti-inflammatory drug (NSAID) use and use of antacid medications to relieve the discomfort.
Peptic duodenitis is associated with acid injury and leads to a spectrum of histological mucosal changes that may be difficult to distinguish from that seen in coeliac disease. [39] For this reason it is recommended that biopsies are not taken in the duodenal bulb, but rather in the second or third portion of the duodenum, which are relatively protected from peptic injury.
Crohn's disease
Crohn's disease can affect any part of the gastrointestinal tract and symptoms may be extremely variable.
The classical findings on histological examination include granulomas, ulcerations, and acute and chronic inflammation often extending throughout all layers of bowel wall.tTG serology is usually negative and there should be no response to gluten withdrawal.
Giardiasis
Giardiasis is a diarrhoeal illness caused by infection with a waterborne parasite, Giardia lamblia. A history of exposure to contaminated water may suggest the diagnosis. [40]
Multiple stool specimens usually reveal the parasite. Alternative methods for detection are antigen detection tests by enzyme immunoassays and detection of parasites by immunofluorescence. [40]
Small-intestinal bacterial overgrowth
History may show conditions that alter intestinal anatomy, motility, and gastric acid secretion (such as use of proton pump inhibitors or anatomical disturbances in the bowel, including fistulae, diverticula, and blind loops created after surgery). [41]
The definitive investigation requires culture of jejunal fluid that grows in excess of 10^5 bacteria/mL. Hydrogen breath testing may show malabsorption but is not very sensitive or specific for bacterial overgrowth. A trial of treatment with antibiotics for 1 week may give the diagnosis. [42]
Post-gastroenteritis
In some children a clinical episode indistinguishable from acute gastroenteritis is followed by protracted diarrhoea. This may be related to prolonged rotavirus infection, [43] or transient lactose intolerance.
Usually no investigations are required.
Eosinophilic enteritis
Eosinophilic enteritis may affect any part of the alimentary canal and can present with anaemia, diarrhoea, abdominal pain, and weight loss. Often no cause is identified, although nematode infections are often isolated. [44]
Diagnosis follows endoscopic or laparoscopic biopsy of the affected bowel with histology showing eosinophilic infiltrates. [44]
Tropical sprue
Tropical sprue is a disease that causes progressive villus atrophy in the small intestine that is similar to coeliac sprue. It is believed to be initiated or sustained by a still-undefined infection. The relapse rate is substantial in treated patients who remain in, or return to, endemic areas in the tropics. [45]
Antibiotic therapy with tetracyclines for 6 months normalises mucosal structure in the small intestine. [45]
CVID and other immunodeficiency states
Common variable immune deficiency (CVID) and related disorders have a history of recurrent infections.
Negative tTG serology and decreased immunoglobulin levels suggest immunodeficiency.
GVHD
Graft-versus-host disease (GVHD) can occur with any organ transplantation but is most common after bone marrow transplantation. Patients have high-volume watery diarrhoea about 3 weeks after transplantation if GVHD is present. [46]
Endoscopic biopsy showing the presence of increased numbers of apoptotic epithelial cells in the intestinal crypts is diagnostic. [46]
Autoimmune enteropathy
This condition is characterised by villous atrophy that is unresponsive to any dietary restrictions. [47]
Negative for immunoglobulin A anti-gliadin and anti-endomysial antibodies.Immunofluorescence staining may show enterocyte antibodies. [47]

Colonic polyps

Colorectal cancer
Weight loss, loss of appetite, and change in bowel habit are more likely to occur with a colorectal cancer (CRC) than a simple polyp, as are obstruction and bleeding. Proctoscopic or rigid sigmoidoscopic examination may demonstrate the lesion and allow clinical differentiation between the 2 conditions.The features at proctoscopy or rigid sigmoidoscopy that may demonstrate CRC include ulceration, contact bleeding, heterogenous shape, or coloration of the lesion.
Endoscopic and histological assessment of the lesion will definitively differentiate between polyps and invasive cancers, although a larger polyp may not be definitively differentiated from cancer without colonic resection, as definitive histological examination of the polyp specimen may be inadequate.Histologically, invasion through the muscularis mucosae would define CRC. Endoscopic features that may demonstrate CRC include ulceration, contact bleeding, heterogenous shape, or coloration of the lesion.
Haemorrhoids
May present with bright red rectal bleeding in association with defecation or straining at stool, perianal pain or discomfort, and anal pruritus. A palpable anal mass may be present.Haemorrhoids can mimic a distal polyp by causing bright red rectal bleeding.
Endoscopy: presence of haemorrhoid; however, this does not rule out concurrent polyps or cancers, and further endoscopic examination should be done.
Anal fissure
Severe pain is experienced on defecation, and fresh blood is usually present on wiping. Anal fissures can mimic a distal polyp by causing bright red rectal bleeding.
Endoscopy: presence of anal fissure; however, this does not rule out concurrent polyps or cancers, and further endoscopic examination should be done.
Crohn's disease
May present with fatigue, diarrhoea, abdominal pain, weight loss, fever, and rectal bleeding. Other signs may include presence of oral ulcers, perianal skin tags, fistulae, abscesses, and sinus tracts; no mass present on digital rectal examination.
Endoscopic examination: inflammation can lead to pseudo-polyps, which are areas of inflammation and ulceration surrounding a relatively spared area that appears to be raised and polypoid.Other features at colonoscopy include aphthous ulcers, mucosal inflammation with hyperaemia and oedema, 'cobblestone' appearance, and 'skip lesions'.Histology of full-thickness bowel biopsy: transmural involvement with non-caseating granulomas.
Ulcerative colitis
May present with bloody diarrhoea, hx of lower abdominal pain, faecal urgency, presence of extra-intestinal manifestations (e.g., erythema nodosum, acute arthropathy), hx of primary sclerosing cholangitis; no mass present on digital rectal examination.
Endoscopic examination: inflammation can lead to pseudo-polyps, which are areas of inflammation and ulceration surrounding a relatively spared area that appears to be raised and polypoid.Other features of ulcerative colitis at colonoscopy include continuous uniform involvement of the mucosa and including the rectum, loss of vascular marking, diffuse erythema, mucosal granularity, normal terminal ileum (or mild 'backwash' ileitis in pancolitis); fistulas are rarely seen.Histology of biopsy: evidence of disease continuing distally, mucin depletion, basal plasmacytosis, and diffuse atrophy of the mucosa; the anus is spared and there are no granulomas.

Colon adenocarcinoma

Irritable bowel syndrome (IBS)
A clinical diagnosis is based on the Rome III Criteria that specify at least 3 months' duration, with onset at least 6 months previously, of recurrent abdominal pain or discomfort associated with 2 or more of: improvement in abdominal pain with defecation, change in frequency of stool, change in form (appearance) of stool.
There is no specific diagnostic test for IBS.Patients who fulfil the clinical criteria for IBS and have no alarm features have a very low probability of organic disease. Colonoscopy or colonic imaging is recommended for patients older than 50 years of age due to higher pre-test probability of colorectal cancer. [65]
Ulcerative colitis
Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer. Patients with inflammatory bowel disease frequently have watery diarrhoea. However, patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment.
Colonoscopy will show rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, normal terminal ileum (or mild 'backwash' ileitis in pancolitis).
Crohn's disease
Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer. Patients with inflammatory bowel disease frequently have watery diarrhoea. Patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment.
Colonoscopy with intubation of the ileum is the definitive test to diagnose Crohn's disease and will show mucosal inflammation and discrete deep superficial ulcers located transversely and longitudinally, creating a cobblestone appearance. The lesions are discontinuous, with intermittent areas of normal-appearing bowel (skip lesions).
Haemorrhoids
Causes bright red rectal bleeding that is separate from the stool. There is no abdominal discomfort or pain, altered bowel habits, or weight loss.
Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age.
Anal fissure
Severe pain on defecation. Blood is usually on wiping. There is no abdominal discomfort or pain, altered bowel habits, or weight loss.
Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age.
Diverticular disease
Diverticular stricture or inflammatory mass may be clinically indistinguishable from colorectal cancer.
Colonoscopy with biopsies and CT imaging will usually differentiate.

Colorectal cancer

Irritable bowel syndrome (IBS)
A clinical diagnosis is based on the Rome III Criteria that specify at least 3 months' duration, with onset at least 6 months previously, of recurrent abdominal pain or discomfort associated with 2 or more of: improvement in abdominal pain with defecation, change in frequency of stool, change in form (appearance) of stool.
There is no specific diagnostic test for IBS.Patients who fulfil the clinical criteria for IBS and have no alarm features have a very low probability of organic disease. Colonoscopy or colonic imaging is recommended for patients older than 50 years of age due to higher pre-test probability of colorectal cancer. [65]
Ulcerative colitis
Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer. Patients with inflammatory bowel disease frequently have watery diarrhoea. However, patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment.
Colonoscopy will show rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, normal terminal ileum (or mild 'backwash' ileitis in pancolitis).
Crohn's disease
Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer. Patients with inflammatory bowel disease frequently have watery diarrhoea. Patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment.
Colonoscopy with intubation of the ileum is the definitive test to diagnose Crohn's disease and will show mucosal inflammation and discrete deep superficial ulcers located transversely and longitudinally, creating a cobblestone appearance. The lesions are discontinuous, with intermittent areas of normal-appearing bowel (skip lesions).
Haemorrhoids
Causes bright red rectal bleeding that is separate from the stool. There is no abdominal discomfort or pain, altered bowel habits, or weight loss.
Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age.
Anal fissure
Severe pain on defecation. Blood is usually on wiping. There is no abdominal discomfort or pain, altered bowel habits, or weight loss.
Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age.
Diverticular disease
Diverticular stricture or inflammatory mass may be clinically indistinguishable from colorectal cancer.
Colonoscopy with biopsies and CT imaging will usually differentiate.

Common cold

Hayfever (allergic rhinitis)
Rhinitis occurs in response to exposure to specific allergens.Chronic fluctuating course, according to allergen exposure and seasonal pattern.The presence of sore throat would make a common cold more likely.Other features of atopy suggestive of condition.
Allergen skin patch testing and in vitro specific IgE determination are diagnostic tests.
Chronic sinusitis
Symptoms longer than 6 weeks. Usually diagnosed with the aid of radiological studies. Common clinical characteristics of chronic sinusitis include hyposmia or anosmia.More commonly characterised by chronic inflammation than a bacterial infection, especially in adults.
Sinus CT scans are abnormal in sufferers of chronic sinusitis.
Streptococcal tonsillitis
Use of the McIsaac score can help to discriminate; a score of 2 or 3 should lead to obtaining a throat swab. [18]Tender anterior cervical glands, tonsillar swelling or exudates, absence of cough, temperature is greater than 38°C (>100.4°F), and age under 15 years.
A positive throat culture for streptococcus confirms the diagnosis in most cases.
Acute sinusitis
Acute disease often due to an infectious cause.Usually clinically diagnosed and may present with nasal congestion, cough, discoloured nasal mucous, and facial pressure/pain.Facial tenderness is a rare and unreliable sign; however, reproducible pain on percussion of frontal and maxillary sinuses strongly indicates acute bacterial sinusitis.
Diagnosis is clinical.
Infectious mononucleosis (mono)
Often subclinical in young children.Well-described syndrome with maculopapular rash, fatigability, fever, laryngitis, and malaise.Hepatosplenomegaly common.
Lymphocytosis on FBC.Positive heterophile antibody test usually diagnostic; may be false-negative in early stages of the illness.EBV antibody titres can help differentiate acute and chronic forms of EBV infection.
Influenza
Fever, headache, muscle aches, and malaise are predominant features.Symptoms more severe than URTI.Fever greater than 38°C (>100.4°F) suggestive in adults.May lead to prolonged period of absenteeism/inactivity.Can lead to severe complications in elderly and immunocompromised.
Viral culture, direct immunofluorescent-antibody staining, and reverse transcriptase-PCR are recognised tests.
H1N1 influenza ('swine fl')
Causes clinical features typical of influenza (fever, cough, sore throat, muscle aches, malaise), usually in a community where H1N1 swine influenza is circulating or in someone who has travelled to such a community.
Viral culture, direct immunofluorescent-antibody staining, and reverse transcriptase-PCR will detect influenza virus. The most definitive means of identifying H1N1 influenza A virus is specific real-time reverse transcriptase-PCR testing that can be performed at specialist laboratories. It can be done directly on patient specimens (e.g., nasopharyngeal swab or aspirate, nasal wash and swab, or tracheal aspirate) or on cultured virus from patient specimens.
Pertussis
Initial upper respiratory symptoms may give way several weeks later to an increased severity of cough, with paroxysmal coughing first increasing in frequency, then remaining constant for several weeks. There may be inspiratory whooping and post-tussive vomiting. Inspiratory stridor may be heard on auscultation.
Evidence of Bordetella pertussis from nasopharyngal swabs or aspirates.
Diphtheria
May be a history of exposure or travel to endemic area.Sore throat and low-grade fever (usually <39°C [<102°F]) followed by dysphagia, dysphonia, dyspnoea, and a croupy cough if there is extension of the pseudomembrane and/or involvement of the posterior pharyngeal and laryngeal nerves.Grey-brown pseudomembrane may form over the tonsils and/or pharynx after 2 to 5 days of sore throat. Without treatment, it can thicken and spread. Neck swelling and lymphadenopathy may cause characteristic bull-neck appearance.
Microscopy and cultures from nose and throat swabs, taken when possible from beneath the pseudomembrane, positive for Corynebacterium diphtheriae.
Meningococcal disease
May present with non-specific respiratory signs/symptoms.As the illness develops, thirst, respiratory distress, a petechial rash, peripheral vasoconstriction, altered consciousness, photophobia, hypotonia, neck stiffness, seizures, and tachycardia may be present.In infants, a bulging fontanelle and a characteristic high-pitched cry may occur.A positive Kernig's or Brudzinski's sign indicates meningeal inflammation and is suggestive of meningitis; is present only in a minority of patients.
Isolation of Neisseria meningitidis from a sterile body site (blood, CSF, joint, pleural fluid, pericardial fluid, or aspiration or biopsy of a purpuric lesion) is the definitive test for diagnosis of invasive meningococcal infections.
HIV seroconversion illness
Between 50% and 90% of HIV-infected individuals develop an acute clinical illness that typically occurs 2 to 4 weeks after exposure to HIV.Often recognised in retrospect since features are non-specific.Onset is acute and lasts up to 2 weeks.Common symptoms are a glandular fever-type illness with fever, malaise, myalgia, pharyngitis, headaches, diarrhoea, neuralgia or neuropathy, lymphadenopathy, maculopapular rash, and mucocutaneous ulceration.
Humoral immunodeficiency shows low immunoglobulin levels. Cellular immunodeficiency indicates T-cell dysfunction and/or HIV.

Common cutaneous drug reactions

SLE
SLE usually occurs in young women; drug-induced lupus can occur in anyone.SLE commonly involves the kidneys, drug-induced lupus rarely.
FBC: anaemia, leukopenia, thrombocytopenia; rarely pancytopenia. (Drugs and infections should be excluded as a cause.)Serum complement: often low.SLE is associated with antibodies to double-stranded DNA; drug-induced lupus is associated with antibodies to single-stranded DNA.
Psoriasis
Typically presents as erythematous, circumscribed, scaly papules and plaques on elbows, knees, extensor surfaces of limbs, and the scalp.
Skin biopsy shows that psoriasiform lesions caused by practolol are accompanied by fibrosis, which is not normally a feature of psoriasis.
Lichen planus
Cutaneous lichen planus typically presents with intensely pruritic lesions on flexor wrists, ankles, trunk, and extremities.
Biopsy of lesional skin for histopathology shows lymphohistiocytic infiltrate and necrotic keratinocytes with hyperorthokeratosis and hypergranulosis in non-drug-induced lichen planus.In lichen planus, parakeratosis, spongiosis, and patchy inflammatory changes suggest a drug-induced cause.
Other non-drug-related rashes
Differential diagnosis of any drug-related rash is the non-drug-related form of the condition that it looks like; in a few cases, such as SLE, psoriasis, and lichen planus, features help to distinguish drug-related from non-drug-related rashes.
Peripheral blood eosinophilia and an eosinophilic cellular infiltrate in any lesion suggest a drug-related effect.Exanthematous reactions are often due to infections; a specific diagnosis may be possible if the causative organism can be identified.

Common hereditary lysosomal storage diseases

Langerhans cell histiocytosis (DDx of type 2 and 3 Gaucher's disease)
There may be symptoms of diabetes insipidus (polyuria/polydipsia).
Tissue biopsy shows proliferation of Langerhans cell histiocytes.
Rheumatic fever (DDx of Fabry's)
Recent sore throat or scarlet fever; fever.
Rapid antigen test positive for group A Streptococcus.
Bacterial endocarditis (DDx of Fabry's)
Fever; historical sources of bacteraemia (IV drug use, indwelling vascular catheters, recent dental work).
Blood cultures show bacteraemia.
Migraine (DDx of Fabry's)
Sensitivity to light and noise; aura.
Laboratory tests can only exclude other differentials of migraine.
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (DDx of Fabry's)
Hx of migraine, hx of TIA/stroke.
MRI shows lesions around basal ganglia, periventricular white matter, and pons.
Rheumatoid arthritis (DDx of mucopolysaccharidosis)
Mean age of presentation 50 to 55 years.
Positive for rheumatoid factor.
Amyloidosis (DDx of mucopolysaccharidosis)
Jugular venous distension, lower extremity oedema, periorbital purpura, macroglossia.
Monoclonal protein in serum or urine immunofixation.
Alzheimer's dementia (DDx of Tay-Sachs)
Advanced age.
Tests can rule out other causes of dementia.
Muscular dystrophies (DDx of Pompe's)
FHx of a muscular dystrophy.
Serum CK may be 50 to 100 times normal level. Xp21 mutation present in Duchenne's muscular dystrophy.

Common toxic plant ingestions

Viral gastroenteritis
Usually insidious onset, accompanied by fever and other constitutional signs and symptoms. Self-limiting. Commonly caused by rotaviruses, noroviruses, and certain adenoviruses.
Viral stool culture: positive for causative organism.
Bacterial gastroenteritis
Usually accompanied by ingestion of spoiled food contaminated with staphylococcus, salmonella, campylobacter, or other bacterial pathogens.
Stool culture and culture of suspected food: positive for causative organism.
Acute myocardial infarction
May be difficult to differentiate clinically.History of CAD, presence of cardiac risk factors.
ECG: ischaemic changes.Cardiac enzymes: elevated.
Epilepsy
May have known history of seizures.
EEG: epileptiform activity or focal, localising abnormality.
Cyanide poisoning
May be difficult to differentiate clinically (chronic cassava or prunus seed ingestion can cause cyanide toxicity). History of occupational exposure.Cherry-red colour to lips and skin. May rarely smell bitter almonds on breath. Hypotension.
ABG: acidosis, elevated lactate.
Paracetamol poisoning
History of deliberate overdose or chronic ingestion. May cause various degrees of liver injury including fulminant hepatic failure and hepatorenal syndrome.
Serum acetaminophen levels: may be elevated.

Common warts

Flat warts
Flesh-coloured, flat-topped, slightly raised papules.Usually multiple and found on extremities or face.
No differentiating tests.
Palmoplantar warts
Palmoplantar warts are endophytic and occasionally tender, with scale and black dots on the surface, and commonly found on palms and soles.
No differentiating tests.
Seborrhoeic keratosis
Lesions are greyish-brown stuck-on scaly papules with white pseudocysts and a smooth or rough surface.Many are present in the same skin area and persist indefinitely.
No differentiating tests.
Acquired digital fibrokeratoma
Lesions occur on the digit, and have a firm, smooth surface.There are no tiny black dots on the surface.
No differentiating tests.
Clavus
Lesions occur on the digit in the areas of friction and over bony prominences and have a firm, rough surface.There are no tiny black dots on the surface.
Skin biopsy shows hyperkeratosis and parakeratosis with central epidermal atrophy, plus peripheral acanthosis and possible perivascular infiltrates of the upper dermis.
Callus
Lesions occur on the digit in the areas of friction and over bony prominences and have a firm, rough surface.There are no tiny black dots on the surface.
Skin biopsy shows hyperkeratosis.
Squamous cell carcinoma
Non-healing, enlarging hyperkeratotic papule that becomes inflamed and tender.
Skin biopsy shows parakeratosis, atypical keratinocytes with or without koilocytes.There may be clusters of atypical keratinocytes invading the basement membrane to form small clusters in the papillary or reticular dermis.
HPV-related Bowen’s disease
Non-healing, enlarging hyperkeratotic papule that becomes inflamed and tender. May occur around the nail apparatus, as well as on other skin sites.
Skin biopsy shows parakeratosis, atypical keratinocytes with or without koilocytes.There may be clusters of atypical keratinocytes invading the basement membrane to form small clusters in the papillary or reticular dermis.
Lichen planus
Usually widely spread and pruritic rash.
Skin biopsy shows features characteristic of each lichen planus.
Epidermal naevus
Pruritic plaques
Skin biopsy shows features characteristic of each epidermal naevus.
Melanocytic naevus
Generally brown or tan in colour.There are no tiny black dots on the surface.
Skin biopsy shows features characteristic of melanocytic naevus.
Melanoma
Lesions often have irregular outline, diameter greater than 6 mm, and colour variegation.
Skin biopsy shows features characteristic of melanoma.
Molluscum contagiosum
Lesions appear as umbilicated, pearl-like, smooth papules.At least one third develop symptoms of local erythema, swelling, or pruritus.Seen particularly in immunocompromised patients.
Haematoxyllin and eosin staining shows Henderson Patterson bodies, the definitive histological feature of molluscum contagiosum.
Tuberculosis verrucosa cutis
Wart-like papule with a subtle inflammatory rim at trauma-prone sites, such as hands and digits, as well as lower extremities in children. Lesions enlarge gradually, often in a serpiginous manner, to form a reddish-brown verrucous plaque. Central areas may become fluctuant with pus and keratinaceous debris. After several years, the plaques may heal spontaneously. [3]
Histology shows acute inflammation in the epidermis, pseudoepitheliomatous hyperplasia, microabcesses in the upper dermis, sparce granulomatous foci, and occasional bacilli. [3]

Community-acquired pneumonia

Hospital-acquired pneumonia
History of being hospitalised or institutionalised is the differentiating factor; everything else would be similar to CAP.Possibly different pathogens.Hospital-acquired aspiration pneumonia is caused by aspiration of oral and gastric secretions into the bronchial tree.Aspiration pneumonia is more prevalent in patients who are debilitated. Treatment needs to include antibiotics for Pseudomonas and anaerobic organisms.
Laboratory tests will identify pathogens.
Tuberculosis
Recent travel to endemic area, exposure to TB-infected patient.
Granuloma formation. CXR may show cavity and/or upper-lobe predominance.Positive tuberculin PPD skin testing.
COPD exacerbation
Worsening of underlying lung disease.Increased wheezing, coughing, SOB and diminished pulse oximetry.
CXR shows hyperinflation.
CHF exacerbation
History of heart failure, SOB, ankle oedema.
CXR shows pulmonary congestion and/or pleural effusions.Beta-natriuretic peptide levels are elevated.
Pneumothorax
Sudden onset of SOB and chest pain.
CXR shows air in pleural space.
2009 influenza A (H1N1) virus
Febrile respiratory illness with fever and cough. Other common symptoms are shortness of breath, fatigue or weakness, chills, myalgia, rhinorrhoea, sore throat, and headache. Vomiting and diarrhoea are relatively common presenting symptoms.
Testing is not necessary for all patients who present with influenza-like illness.Definitive diagnosis can be made with real-time reverse transcriptase-PCR (rRT-PCR) of respiratory specimens or viral culture using panels that probe for human and swine influenza A.
Seasonal influenza infection
Sudden onset of febrile respiratory illness characterised by upper and lower respiratory tract symptoms of rhinorrhoea, cough, fever, chills, headache, and myalgia.Typically presents in winter season.
The criterion standard for diagnosing influenza A and B is a viral culture of nasopharyngeal samples and/or throat samples; however, most physicians diagnose influenza based on clinical criteria alone.

Compartment syndrome of extremities

Deep vein thrombosis
Erythaema, collateral superficial veins, Wells score ≥2.
Ultrasound may detect thrombus in paired posterior tibial veins, paired anterior tibial veins, and paired peroneal veins.D-dimer may be raised.
Stress fracture
Significant tenderness to palpation over the fractured site.
X-ray shows fracture. Compartment pressure is normal.
Acute ischaemia
Hx of claudication and absence of peripheral pulses.
Duplex ultrasound may show peak systolic velocity ratio >2.0. Continuous-wave Doppler ultrasound may show pulsatility index decrease between adjacent proximal and distal anatomical segments.Compartment pressure is normal.
Chronic venous insufficiency
Obvious varicose veins on physical examination.
Duplex ultrasound, assessing for reversed flow, may show valve closure time >0.5 second (indicating reflux).Compartment pressure is normal.
Muscle tear
Significant tenderness to palpation over affected muscle; possible overlying ecchymosis.
Ultrasound may demonstrate grading of muscle damage: generalised or focal hyperechogenicity (grade 1), interruption of fibres in the echogenic perimysial striae (grade 2), rounded and hyperechogenic appearance of muscle stump (grade 3).Compartment pressure is normal.
Haematoma
Tenderness to palpation and possible overlying ecchymosis.
Compartment pressure is normal.
Extremity fracture
Significant tenderness to palpation over the fractured site. Absence of tight compartment on physical examination.
X-ray shows the fracture. Compartment pressure is normal.
Tight casts, dressings, external wrappings
Relief of symptoms with removal of casts, dressings, wrappings.
Differentiating tests not needed if symptoms improve after removal of casts, dressings, wrappings.

Compartment syndrome of the abdomen

shock
Shock can be clinically indistinguishable from abdominal compartment syndrome (ACS) and significant overlap exists, since patients develop ACS from excess fluid resuscitation given to treat hypovolaemic or septic shock.
Intra-abdominal pressure (IAP) is normal.
acute tubular necrosis
Acute tubular necrosis is clinically indistinguishable from ACS, although may have a history of exposure to nephrotoxic agents.This condition can also occur as a complication of ACS.
The IAP is normal.Urinalysis may show granular casts.Renal biopsy shows characteristic features.
acute renal failure
Renal failure is clinically indistinguishable from ACS.The condition presents with oliguria in many of the same patient populations that are at increased risk for ACS.It can also occur as a complication of ACS.
The IAP is normal.Renal ultrasound shows dilated renal calyces (suggesting obstruction) or reduced corticomedullary differentiation.Renal biopsy reveals intra-renal causes.
adult respiratory distress syndrome
Patients have cough with expectoration of frothy pulmonary oedema.Basilar or diffuse rales are present on chest auscultation.Patients generally require higher levels of oxygen and/or PEEP to maintain oxygen saturation >90% than patients with ACS.
IAP is normal or mildly elevated (due to pressure transmission from torso to abdomen).Chest x-ray shows contusion and new bi-lateral interstitial infiltrates suggestive of pulmonary oedema.

Complex regional pain syndrome

Peripheral neuropathy due to a metabolic cause
Underlying diabetes mellitus, renal failure, alcoholism, or malnutrition.Symptoms of pain, burning, and hyperalgesia are symmetrical and tend to begin in the distal lower extremities and affect the upper extremities later.There is usually no history of trauma, and most peripheral neuropathies progress gradually.If large fibres are involved there is a loss of reflexes, weakness, and vibratory and proprioceptive deficits.
Nerve conduction studies and EMG reveal abnormal action potentials detected symmetrically.Elevated urea and creatinine with renal failure.Elevated fasting blood glucose >125 mg/dL with diabetes mellitus.
Focal or entrapment neuropathies
Symptoms and signs are confined to the distribution of the affected nerve (e.g., carpal tunnel, cubital tunnel, or thoracic outlet syndrome).No history of trauma.
Usually a clinical diagnosis.Nerve conduction abnormalities confined to the affected nerve and its innervated musculature.MRI reveals a high-intensity signal at point of entrapment. Only useful for large nerves (e.g., ulnar).
Deep vein thrombosis
Swelling, pain, and discoloration of the affected extremity. Burning, electrical, or shooting pains are uncommon.
Compression ultrasonography shows non-compressibility of vascular lumen on gentle pressure.Impedance plethysmography may reveal a reduction in venous emptying and consequent slower rise in impedance. Result is operator-dependent.
Thrombophlebitis
Focal pain, swelling, tenderness, erythema, and a palpable cord in the affected vein.
Usually a clinical diagnosis.Compression ultrasonography may be used to detect spread of inflammation to deep veins.
Lymphoedema
Often secondary to surgery, radiation, or infection. Onset is insidious; oedema is non-pitting; pain is usually aching in nature.
Lymphoscintigraphy outlines the anatomy of the lymphatic system and identifies areas of obstruction to flow.
Gout
Affects joints, most commonly the big toe.Sudden onset; may have history of symptoms or gouty tophi visible in long-standing hyperuricaemia.
Usually a clinical diagnosis.Synovial fluid aspirate shows monosodium urate crystals.
Pseudogout
Can present as acute mono-articular arthritis or a poly-articular symmetrical arthritis similar to rheumatoid arthritis. Typically affects shoulders and wrists.
Synovial fluid aspirate shows calcium pyrophosphate crystals.
Scleroderma
Accompanied by other features of scleroderma: skin tightness, calcinosis, itching, Raynaud's syndrome, or elevated blood pressure.
Presence of antinuclear antibodies on serological testing.
Tenosynovitis due to spondyloarthropathy (e.g., ankylosing spondylitis)
Pain to palpation at site of tendon insertion; common sites include Achilles tendon and insertion of plantar fascia onto calcaneus.Associated features of a spondyloarthropathy (e.g., morning stiffness, fatigue, low-grade fever, low back pain, or extra-articular manifestations).
Diagnosed on clinical criteria and radiographic findings of bony erosion and periosteal new bone formation.HLA-B27 antigen positive in majority of cases but not usually tested.

Concussion

Severe/moderate traumatic brain injury
Observed loss of consciousness lasting >30 minutes, post-traumatic amnesia lasting >24 hours. [4] [3] Other differentiating features may include cervical spine injury, skull fracture, and intra-cranial bleed.Glasgow Coma Scale score 12 or under. [4] [3]
Positive CT/MRI results can be used in the semi-acute phase, especially in cases of worsening symptoms, to rule out structural damage, including skull fracture and other intra-cranial abnormalities (mid-line shift, haemorrhaging).
Depression
Physical symptoms may be similar, but there is no precipitating head injury.Can be confirmed on history taking. [4] Screening questionnaires can be used.
Diagnosis is clinical.
General trauma or injury to the body not involving the head
Physical symptoms may be similar, but there is no precipitating head injury.Can be confirmed on history taking and physical examination. [4]
Diagnosis is clinical.
Headache disorders
These can include trauma-induced migraines. Although similar in symptomatology, headache disorders are a different disorder in pre-morbid cases, and in trauma-induced cases require the inclusion of a neurologist or physiatrist for proper management.Can be confirmed on history taking. [4]
Diagnosis is clinical.

Congenital adrenal hyperplasia

Addison's disease
Patients with Addison's disease tend to have symptoms of muscle weakness and fatigue. CAH does not exhibit these signs and symptoms.
In Addison's disease, an ACTH stimulation test will show a poor or absent cortisol response. Other adrenal hormones also do not exhibit a stimulated response.
Gender identity disorder
Patients with gender identity disorder have confusion and anxiety about their gender and tend to feel they were assigned the wrong sex. Also, cross-dressing is common. These symptoms are not associated with CAH.
Laboratory tests tend to be normal in gender identity disorder, whereas CAH shows abnormal response to the ACTH stimulation test.
Familial glucocorticoid syndrome
Patients with familial glucocorticoid syndrome may present with pallor, sweating, palpitations, hunger, visual changes, or mental status changes, symptoms not shared by CAH.
Patients with familial glucocorticoid syndrome have normal blood chemistry, but classical CAH shows a hyponatraemic, hyperkalaemic, metabolic acidosis.
Renal salt-wasting
Renal salt-wasting is associated with a history of diuretic use and/or uncontrolled diabetes mellitus, not typically shared by patients with CAH.
In renal salt-wasting, 17-hydroxyprogesterone is normal and in CAH this is high.

Congenital torticollis

Superior oblique palsy
Children with congenital superior oblique palsy, also known as ocular torticollis, tend to tilt their head away from the side of the weak superior oblique muscle to restore binocular vision. On examination, if the head is passively tilted toward the affected side, hypertropia or vertical deviation of the eye may be seen, but this is not always obvious. [3]
Ophthalmological examination: hypertropia on contra-lateral side.
CNS tumour
Intermittent torticollis associated with neurological symptoms may indicate a posterior fossa or spinal cord tumour. [5]
Cranial/cervical spine MRI: posterior fossa or spinal cord tumour.
Vertebral anomaly
Children with congenital vertebral segmentation anomalies such as hemi-vertebrae or Klippel-Feil syndrome present with a head tilt and can have associated cervico-thoracic scoliosis. There may be more fixed deformities noted on physical examination.
Cervical spine x-ray: cervico-thoracic scoliosis.
Craniosynostosis
Cranial asymmetry resulting from craniosynostosis is not typical of that seen in congenital muscular torticollis with positional plagiocephaly. For example, posterior plagiocephaly produces a parallelogram-shaped head while unilateral lambdoid synostosis produces a trapezium-shaped head. [24]
Skull x-ray or CT: features of craniosynostosis.

Constipation

Anal fissure
Rectal pain, bleeding, excessive straining.
Diagnosed clinically by digital rectal examination.
Medicine-induced constipation
Temporal relationship of the onset of symptoms with medicine use.Medicines include opiates, calcium channel blockers, and antipsychotics.
Withdrawal of offending medicine may improve symptoms of constipation.
Hypercalcaemia
Tiredness, nausea, vomiting, loss of appetite.
Corrected serum calcium level >2.75 micromols/L (>11 mg/dL).
Hypothyroidism
Weight gain, dry skin, depression, fatigue, changes in voice.
TSH level elevated in primary hypothyroidism; low in central hypothyroidism.
Diabetes mellitus
Polyuria, polydypsia, polyphagia.
Fasting blood sugar: 6.9 mmol/L (126 mg/dL) or higher.HbA1c 6.5% or higher.Random plasma glucose: 11 mmol/L (200 mg/dL) or higher in presence of symptoms of polyuria, polydipsia, and unexplained weight loss.Abnormal oral glucose tolerance test.
Spinal cord lesion
Motor and/or sensory changes in the affected areas of the body.
Imaging of the spinal cord with a CT scan or MRI may help to identify the location and severity of the lesion.
Colonic stricture
Changes in bowel habit, including bowel calibre; gradual onset of symptoms.
Endoscopic diagnosis by direct visualisation or by barium enema.
Colon cancer
Weight loss, melaena, haematochezia, changes in bowel habit.
Endoscopic diagnosis by direct visualisation or by barium enema/CT.
Parkinson's disease
Rigidity, akinesia, tremor.
Clinical diagnosis.

Constipation in children

Hirschsprung's disease
Neonatal onset with failure to pass meconium within 24 hours, abdominal distension, vomiting, and subsequent failure to thrive.
Rectal mucosal biopsy showing increased acetylcholinesterase-positive nerves and an absence of ganglion cells in the myenteric plexus.
Anorectal anomaly
Position of the anus is ectopic or absent.
Examination under anaesthetic and imaging shows degrees of ectopia, covered anus, rectovaginal fistula, or types of imperforate anus.
Group A streptococcal perianal skin infection
Bright red erythema and local oedema.
Growth of the organism from skin swab culture.
Anal fissure
Generally associated with history of fresh blood on stool or nappy, and skin tag. Characteristically in midline directly anterior or posterior.
Diagnosis is based on clinical appearance.
Lichen sclerosis et atrophicus
Thickened whitish perianal and vulval skin associated with deep fissures.
Positive response to topical corticosteroids.
Anal sexual abuse
Disclosure may be withheld but fissure may extend beyond anal margin and in lateral positions.Depending on time from assault, there may be redness or bruising locally.Reflex anal dilation may be seen but should not be confused with the reflex relaxation of the internal sphincter seen with a faecally impacted rectum.
Expert multi-disciplinary disclosure interviews and forensic examination to seek semen or evidence of sexually transmitted diseases.
Myotonic dystrophy
Dramatically gaping anus often in association with constipation. Evidence of myopathic facies, motor delays, cataract, or premature frontal balding. Presence of family history of myotonia.
Genetic testing confirms the diagnosis.
Neuropathic bowel
Low anal sphincter tone when rectum loaded, poor ankle reflexes, and sometimes sacral or lumbar spine haemangioma or skin defects.
MRI scan of spine may show degrees of spinal dysraphism, thickening of cauda equina, cord tethering, or intraspinal tumour or syrinx.
Cows' milk intolerance
Anus may appear reddened, and other signs of atopy (e.g., eczema) may be present.
Positive skin tests or specific IgE tests and resolution of constipation during exclusion diet.
Gluten enteropathy (Coeliac disease)
Usually associated with poor weight gain.
Positive coeliac screening (i.e., anti-tissue transglutaminase [TTG] IgA, anti-endomysial [EMA] IgA) and atrophic jejunal mucosa on biopsy.
Crohn's disease
Fleshy skin tags and local oedema with deep fissures often associated with abdominal pain, poor weight and growth, and oral lesions.
Endoscopy, biopsy, radio-isotope scan. Findings suggestive of Crohn's disease include submucosal oedema, rigidity, pseudodiverticulae, or fistulisation. Deep ulcerations result in a cobblestone appearance.
Hypothyroidism
Usually pan-colonic delayed transit constipation in association with poor height velocity and associated conditions such as diabetes mellitus in older children.
Elevated TSH (this is the most important in this age range).Generally positive anti-thyroid antibodies, as neonatal hypothyroidism is detected by screening before the onset of constipation.
Neurofibromatosis
Appearance of skin (i.e., café au lait spots).Megarectum is a recognised complication.
Fibromata may be seen on scans of the CNS.
Williams' syndrome
Characteristic facial features are present (i.e., elfin face with a short and upturned nose and long philtrum of upper lip).
Deletion of one copy of the elastin gene in the 7q11.23 region of chromosome 7 seen on fluorescent in-situ hybridisation.

Contact dermatitis

Atopic dermatitis
Lesions in atopic dermatitis are generally symmetrically distributed over the flexural areas, less likely to be vesicular, more chronic in nature with seasonal variation, and not as sharply delineated.Family history in atopic patients is often positive for atopy.
Patch testing is negative for atopic dermatitis, but may be positive if contact dermatitis and atopic dermatitis co-exist in the same patient.
Nummular eczema
Lesions in nummular eczema are coin-shaped plaques, with pinpoint vesiculation, and symmetrically distributed, most commonly on the extensor lower extremities.
Patch testing is negative in case of nummular eczema.
Dyshidrotic eczema
Dyshidrotic eczema almost exclusively involves the palms and soles, with little to no involvement of the dorsal hands and feet.
Patch testing is negative in cases of dyshidrotic eczema.

Conversion and somatisation disorders

Bipolar disorder
Physical complaints are solely in the context of vegetative symptoms or manic symptoms associated with the mood disorder. Somatic delusions may also be associated with the manic or depressive phase.
Structured clinical interview.
Schizoaffective disorder
Physical complaints are solely in the context of vegetative symptoms or manic symptoms associated with the mood disorder. Somatic delusions may also be associated with the manic or depressive phase.
Structured clinical interview.
Panic disorder
Panic attacks over a 1-month period and associated worry about their implications. Panic attacks involve the sudden onset of intense physical and cognitive symptoms of anxiety that may be triggered by specific cues or occur unexpectedly. Globus hystericus (a sensation of fullness in the neck or difficulty swallowing) or vertigo can sometimes be associated with panic attacks.
Structured clinical interview.
Generalised anxiety disorder
At least 6 months of excessive worry about issues, causing distress or impairment. The anxiety is not confined to features of another mental disorder, nor is it a result of substance abuse or a general medical condition. At least 3 symptoms (or 1 for children) are present most of the time: restlessness or nervousness, easy fatigability, poor concentration, irritability, muscle tension, and sleep disturbance.
Structured clinical interview.
Schizophrenia
Psychosis (i.e., delusions, hallucinations); disorganised speech; negative symptoms (e.g., affective flattening, avolition, anhedonia, attention deficit, or impoverishment of speech and language); or stereotypic behaviour (purposeless repetitive behaviour) occurring for at least 1 month and associated with at least a 6-month period of functional decline. Somatic delusions (fixed false beliefs not belonging to the cultural background of the patient) commonly occur as a part of the illness.
Structured clinical interview.
Hypochondriasis
At least 6 months of unwarranted fear of serious disease, based on misinterpretation of bodily symptoms. Although the fear usually persists despite reassurance, these patients seek reassurance, whereas those with somatisation disorder seek confirmation of illness.
Structured clinical interview.
Body dysmorphic disorder
Preoccupation with physical appearance; patients have strong belief that they have an abnormality or defect in appearance about which they are overly self-conscious; often undergo cosmetic procedures with little satisfaction.
Structured clinical interview.
Somatoform pain disorder
Complaints are limited to pain that cannot be fully attributed to a known medical disorder in at least 1 anatomical site.
Structured clinical interview.
Factitious disorder
Patients feign, deliberately produce, or exaggerate their physical symptoms with intent to assume the sick role.
Structured clinical interview. Evidence of patient actually feigning or willfully producing the illness.
Malingering
Patients consciously fabricate or exaggerate the symptoms of mental or physical disorders for secondary gain (e.g., financial compensation, avoiding work or military service, obtaining drugs, getting out of going to school, or attracting attention or sympathy). Unlike patients with somatoform disorders, they often lack cooperation during diagnostic evaluation. Often associated with antisocial personality disorder.
Structured clinical interview. Neuropsychological battery such as computerised assessment of response bias and test of memory malingering. There is significant discrepancy between claimed illness and appearance or behaviour outside of physician's office.
Dissociative disorder
Although conversion disorder can be conceptualised as a form of dissociation, a dissociative disorder can also include periods of detachment from self or surroundings experienced as 'unreal' or 'outside' of self; periods of time that the patient cannot recall; fugue states; or ≥2 distinct personality states.
Structured clinical interview.
Major depressive disorder
Depression often presents with somatic complaints, particularly in cultures in which mental illness carries a strong stigma. Typical symptoms include dizziness, fatigue, pain, and feelings of inner pressure. A depressive disorder should be considered if these somatic complaints are in the context of other symptoms of depression such as sleep and appetite disturbance, poor concentration, lack of interest or motivation, and/or thoughts of suicide. Psychotic depression can also include somatic delusions, which should be differentiated from a primary somatoform disorder.
Structured clinical interview.
Epilepsy
Positive FHx. Previous CNS infection or trauma. Prior seizure events. Focal neurological symptoms (before or after seizure). Focal neurological deficit. Premonitory sensation or experience. Temporary hemiparesis. Temporary aphasia.
EEG: epileptiform activity or focal, localising abnormality.CT/MRI: may reveal evidence of a structural lesion or other process that has caused the seizure.
Spasmodic dysphonia
Strained or breathy speech. Vocal fatigue.
Fiberoptic laryngoscopy: abnormal delay between onset of electrical and acoustic activity.Stroboscopy: involuntary vocal fold adduction or abduction during connected speech.
Dystonia
Simultaneous contraction of agonist and antagonist muscles. Muscle pain. Appearance of worsening dystonia with action. Blepharospasm. Cervical torticollis. Hand spasm. Foot spasm. Twisting of affected body part. Geste antagoniste (sensory trick).
Levodopa responsiveness: positive if clinical improvement.
Parkinson's disease
Often unilateral. Rigidity. Bradykinesia. Rest tremor. Postural instability. Masked facies.
Dopaminergic agent trial: improvement in symptoms.Olfactory testing: hyposmia or anosmia.
Parkinsonism
Medication with potential extrapyramidal adverse effects. Bradykinesia. Rigidity. Cognitive changes. Autonomic dysfunction.
Improvement with removal of medication with potential extrapyramidal adverse effects.
Multiple sclerosis
Visual disturbance in one eye. Peculiar sensory phenomena. Foot dragging or slapping. Leg cramping. Fatigue. Urinary frequency.
MRI brain: hyperintensities in the periventricular white matter, most-sensitive images are sagittal fluid-attenuated inversion recovery (FLAIR). MRI spinal cord: demyelinating lesions in the spinal cord, particularly the cervical spinal cord; detection of alternate diagnosis, such as cervical spondylosis.
Stroke
Sudden onset of unilateral numbness, weakness, or confusion or visual changes.
MRI/CT brain: ischaemic or haemorrhagic changes.
Dementia
Progressive loss of cognitive functioning, often in multiple domains, which can impair daily activities of living. Occasionally, patients with dementia can also have somatic delusions.
Neuropsychometric testing: dementia-related cognitive changes, and cognitive dysfunction patterns.CT/MRI brain: cerebrovascular lesion with vascular dementia.
Infectious disease
Fever. Recent infectious contact or travel.
WBC, CRP, ESR: elevated.
Autoimmune disease
Genetic predisposition. Immune dysregulation.
Antibody and antigen studies: positive.
Endocrine disorder
Abnormal growth. Weight gain or loss. Fatigue. Mood swings. Altered libido. Polyuria. Polydipsia. Corticosteroid medication.
Electrolyte panel, cortisol, ACTH, glucose, TFTs, triglycerides, cholesterol: may be abnormal.
Heavy metal poisoning
Hx of industrial or environmental exposure. May have neuropathy, hypertension, abdominal pain, psychiatric symptoms, gout, rash.
Urine heavy metal testing: positive.
Vitamin deficiency
Malnutrition. Lack of sunlight.
FBC and vitamin profile: abnormal.
Coeliac disease
Positive FHx. Diarrhoea. Bloating. Abdominal pain.
FBC: reduced Hb.IgA-tissue transglutaminase titre: elevated.Endomysial antibody titre: elevated.
Lactose intolerance
Symptoms after ingestion of dairy products. Diarrhoea. Distention. Mouth ulceration.
Trial of dietary lactose elimination: resolution of symptoms.Lactose hydrogen breath test: breath hydrogen >20 ppm after lactose load and intolerance symptoms.
GORD
Heartburn. Hiatus hernia. Acid regurgitation.
Proton pump inhibitor trial: symptoms improve.EGD: oesophagitis (erosion, ulcerations, strictures) or Barrett's oesophagus.
Paraneoplastic syndrome
Malignancy. Focal neurology.
CT/MRI: evidence of neoplasia/metastases.

COPD

Asthma
Onset of asthma is in early life. A personal or family hx of allergy, rhinitis, and eczema is often present. There is daily variability in symptoms, and patients have overt wheezing that rapidly responds to bronchodilators. Cough variant asthma mimics many features of COPD.
PFTs show reversibility with bronchodilators and no decrease in diffusing capacity of the lung for carbon monoxide (DLCO). Sputum or blood eosinophilia is suggestive of asthma.
Congestive heart failure
Usually a history of cardiovascular diseases is present. Patients report symptoms of orthopnoea, and fine bibasilar inspiratory crackles may be heard on auscultation.
B-type natriuretic peptide levels are usually elevated, and CXR reveals increased pulmonary vascular congestion. Echocardiogram may confirm the diagnosis.
Bronchiectasis
There may be a history of recurrent infection in childhood. Large volume of purulent sputum is usually present. Coarse crackles may be heard on auscultation. History of pertussis or tuberculosis is a clue to diagnosis.
Chest CT reveals bronchial dilation and bronchial wall thickening.
Tuberculosis
A history of fever, night sweats, weight loss, and chronic productive cough is usually present. Tuberculosis is more common in immigrants to non-endemic countries, and in people living in endemic countries.
The diagnosis requires microbiological confirmation. Infiltrates, fibrosis, or granuloma seen on CXR or chest CT may suggest tuberculosis. Patients usually have positive skin test for tuberculosis.
Bronchiolitis
Bronchiolitis affects patients at younger ages. The patient may have a history of connective tissue disorders, especially rheumatoid arthritis, or fume exposure. Some cases are post-infectious.
PFTs in bronchiolitis can present with obstructive (FEV1/FVC is typically >80%), restrictive, or mixed pattern. CXR shows hyperinflation. High-resolution chest CT may show diffuse, small, centrilobular nodular opacities, but is rarely done in children due to radiation risk.
Upper airway dysfunction
Can affect patients of any age. History of prior trauma or intubation is very helpful. Lung examination is usually normal, but signs of upper airway restriction, such as wheezing and stridor, may be present. Patients may have voice hoarseness if vocal cords are involved.
The flow-volume curve in pulmonary function testing may reveal a characteristic expiratory or inspiratory plateau, or both. Diagnosis is confirmed by direct visualisation of the affected airway by endoscopy.
Chronic sinusitis/postnasal drip
Chronic sinusitis/rhinitis is a very common cause of chronic cough. Patients may complain of sinus pressure, rhinorrhoea, non-productive cough, and/or headache.
CT of sinuses and/or empirical trial of antihistamines is commonly utilised to aid in diagnosis.
Gastro-oesophageal reflux disease (GORD)
Patients with GORD often have dyspepsia and frequent belching, and can have a chronic cough that worsens at night when supine.
Diagnosis is usually based on response to empirical therapy with proton-pump inhibitors.
ACE inhibitor
ACE inhibitors can cause chronic cough; however, the cough is usually non-productive.
Diagnosis is usually based on improvement of symptoms after empirical cessation of ACE inhibitor.
Lung cancer
Lung cancer is an important consideration in patients with COPD. Patients may have weight loss, night sweats, haemoptysis, and/or chest or back pain.
Radiography is important in the assessment for lung cancer. Bronchoscopy may be necessary to evaluate for endobronchial cancer if suspicion is high.

Corneal abrasions

Conjunctivitis
Typically presents with a red eye and discharge but without significant pain, photophobia, or changes in vision.No history of trauma.
No definitive test but generally lacks fluorescein uptake on eye examination.
Corneal laceration with globe perforation
Full-thickness lacerations result in a ruptured globe that allows aqueous humour to escape the anterior chamber. The cornea may appear flattened and the pupil may become asymmetric.
Fluorescein applied to a full-thickness lesion changes colour as it is diluted with aqueous humour and streams away from the wound.
Corneal ulceration and ulcerative keratitis
Typically develop over days and have signs of corneal infiltration on examination. Corneal infiltration is a white hazy infiltrate underlying a corneal defect and spreading to adjacent stroma.View image A dendritic pattern may be seen with herpes infection.
An ophthalmologist can scrape the cornea with a sterile spatula or blade and send the sample for smear, cultures, and sensitivity. Gram and Giemsa staining identifies the micro-organisms.
Acute angle-closure glaucoma
Abrupt onset without antecedent trauma, often with severe headache, nausea, and vomiting.Patients typically report alterations in vision with haloes around lights. The eye may have vascular congestion, corneal oedema, and a dilated, unresponsive pupil. Visual acuity is often reduced.
Tonometry: confirms elevated intraocular pressure; >21 mmHg is abnormal.Gonioscopy: trabecular meshwork is not visible, as it is obscured by the peripheral iris.Slit lamp examination: reveals a shallow anterior chamber and a large optic cup, narrowing of the neuroretinal rim, splinter haemorrhage, and nerve fibre loss.
Anterior uveitis
Similar clinical presentation but with no hx of trauma. Pain is usually dull.
Slit lamp examination may reveal signs of protein and WBCs in the anterior chamber (cells and flare), hypopyon or a fluid level of pus, and anterior synechia where the iris adheres to the cornea.FBC, CRP, and ESR are raised as non-specific markers of inflammation.Serum ACE is elevated in patients with sarcoidosis. If the patient is taking angiotensin-converting enzyme (ACE) inhibitors, medication lowers ACE levels.ANAs are positive in patients with juvenile idiopathic arthritis.
UV keratitis
Patients describe some form of excessive UV exposure such as welding, significant sun exposure (solar eclipses or snow fields), or use of suntanning beds.Onset of symptoms is typically 6 to 12 hours after exposure, and the eye appears injected.
Fluorescein staining reveals diffuse superficial punctate epithelial irregularities referred to as superficial punctate keratitis.
Acanthamoeba keratitis
In developed countries, almost always occurs in wearers of contact lenses, though it can also be associated with polluted water or other factors. Often associated with difficulty removing a contact lens.Causes severe pain that is often discordant with the ocular findings.Frequently associated with a ring-shaped infiltrate surrounding a central ulcer.
Definitive diagnosis is by Giemsa stain and culture of a corneal scraping, or identification of Acanthamoeba DNA with polymerase chain reaction.

Costochondritis

Acute coronary syndrome
Severe chest pain-associated dyspnoea, nausea, and diaphoresis. The chest pain may be intermittent and precipitated by exertion.Risk factors for cardiovascular disease (e.g., FHx, hypertension, hyperlipidaemia, diabetes, and smoking) are usually present.
ECG may reveal ST elevation and cardiac enzymes may be elevated. [16]
Pleuritis
Associated dyspnoea and shortness of breath.Decreased breath sounds on auscultation and dullness on percussion.
Chest x-ray may show an effusion.
Pulmonary embolism
Risk factors for thromboembolic disease (e.g., FHx, smoking, OCP use, prolonged immobilisation, or limb trauma).Associated dyspnoea. Haemoptysis may be present. Physical examination may reveal signs of right ventricular dysfunction (e.g., distended neck veins, systolic murmur over left-lower sternal edge, loud pulmonary component of S2). [17]
Elevated d-dimer.CT angiogram showing arterial clot or perfusion/ventilation scan showing mismatch.
Rib fracture
Hx of trauma and tenderness over the rib.
Rib fracture visible on rib-view plain x-rays.
Sternal or clavicular fracture
Hx of trauma, tenderness over sternum or clavicle.
Clavicular or sternal fracture visible on plain x-rays.
Pneumothorax
Hx of sudden-onset dyspnoea and pleuritic chest pain.Decreased chest-wall movement, hyperresonance to percussion, and decreased or absent breath sounds. [18]
Chest x-ray shows a thin, visceral pleural line displaced from the chest wall. [18]
Gastro-oesophageal reflux disease
Symptoms of heartburn and regurgitation.
A therapeutic trial of antacid or proton pump inhibitors may produce improvement.Twenty-four-hour ambulatory pH monitoring may reveal intra-oesophageal pH <4 more than 4% of the time. [19]
Panic disorder
Sudden-onset anxiety, feeling faint, and palpitations. [20]Recurrent, discrete period of intense fear/discomfort. [21]
Clinical diagnosis requiring formal psychiatric assessment.
Generalised anxiety disorder
Hx of worry present most of the time for >6 months.May have a FHx of anxiety. [22]
Clinical diagnosis requiring formal psychiatric assessment.
Depression
Lack of interest in activities and depressed affect for >2 months, insomnia, feelings of worthlessness, excessive guilt, fatigue, poor concentration, and suicidal ideation. [23]
Clinical diagnosis requiring formal psychiatric assessment.
Underlying malignancy
Weight loss, fever, and malaise may be present. There may be local swelling and pain may persist despite treatment. [24] [25]
Chest CT scan showing a mass and/or destruction of the bones and the costochondral joints.
Seronegative spondyloarthropathies
Associated conditions such as psoriasis, inflammatory bowel disease, or sexually transmitted disease.Insidious onset of low-back pain, worse in the morning or after rest. The pain lasts ≥30 minutes and improves with activity.Sacroiliitis may present with bilateral or unilateral buttock pain radiating to the thigh.Physical examination may reveal peripheral inflammatory arthritis, limitation of lumbar-spine movement in frontal and sagittal planes, decreased chest expansion, and anterior uveitis. [26]
Sacroiliac joint x-ray showing indistinct joints, bony erosions, sclerosis, and widening of the joint space.Spinal x-ray showing marginal vertebral body erosions, vertebral body squaring, and syndesmophytes between vertebrae. [26]Radiographic evidence of peripheral erosive arthritis, especially in the case of psoriatic arthritis.Disease-specific evaluation such as dermatology consultation for psoriasis, gastroenterological evaluation, and colonoscopy and/or endoscopy for inflammatory bowel disease.
Fibromyalgia
Widespread body pain.More than 11 of 18 defined tender points are tender upon palpation. [27]
Clinical diagnosis.

Coxiella burnetii infection

Legionella infection
Common symptoms.
Urine antigen test for Legionella will be positive.Negative serology for Coxiella burnetii.
Tularaemia
Common symptoms.
Cultures will be positive for Francisella tularensis.Negative serology for C burnetii.
Viral hepatitis
Patients present with GI symptoms and jaundice.Different risk factors for exposure.
Viral hepatitis serologies (mostly hepatitis A, B, and C) will identify aetiology.Negative serology for C burnetii.
Influenza
No differentiating features in hx and physical examination.
Viral serology or culture may be positive for influenza.Negative serology for C burnetii.
Mycoplasma infection
No differentiating features in hx and physical examination.
Negative serology for C burnetii.

Craniopharyngioma

Pituitary adenoma
Rare in children and adolescents, although quite common in adults.Rarely extend into (as opposed to compressing) the third ventricle and rarely cause hydrocephalus.May be hormone secreting with symptoms consistent with prolactinoma, Cushing's disease, or acromegaly.
MRI/CT: tumour arises from sella with suprasellar extension, or is confined to sella (unlike most craniopharyngiomas) and is nearly always solid and enhancing.Endocrine tests show elevated hormones (dependent upon tumour type).Histopathology provides definitive diagnosis.
Diaphragmatic meningioma
Rare in children and adolescents, more common in older adults.May be no differentiating signs or symptoms.
MRI/CT: homogenous enhancement, enhancing dural 'tail', bony hyperostosis.Histopathology provides definitive diagnosis.
Chiasmatic epidermoid
Paramidline tumours seen in children and young adults.May be no differentiating signs or symptoms.
MRI/CT: lesion off midline, cystic, show restricted water movement.Histopathology provides definitive diagnosis.
Chiasmatic glioma
Most common in infants and children; often seen in association with neurofibromatosis type 1.May be no differentiating signs or symptoms.
MRI/CT: intra-axial tumour of the optic chiasm or nerve, usually non-cystic and may or may not enhance.Histopathology provides definitive diagnosis.
Rathke's pouch cyst, pars intermedia cyst
Uncommon benign embryological malformation.May be no differentiating signs or symptoms.
Histopathology provides definitive diagnosis.
Primary germ cell neoplasm
A malignant CNS neoplasm seen in children, adolescents, and young adults.May be no differentiating signs or symptoms.
Elevated serum and CSF onco-fetal proteins (alpha-fetal protein or beta-human chorionic gonadotrophin).Histopathology provides definitive diagnosis.

CREST syndrome

Generalised morphoea
Non-systemic type of scleroderma; does not involve the fingers. Absence of Raynaud's phenomenon (RP), GORD, and dilated nailbed capillaries.
Serum ANA and rheumatoid factor (RF) present, RF especially in children.Skin biopsy with changes at the dermis and subcutaneous tissues, with an initial inflammatory infiltrate followed by increased collagen bundles, decreased vascularity, atrophy, and an absence of inflammatory infiltrate.
Linear scleroderma
Variable tight skin often along part of an extremity; fingers are usually not involved. [6] RP, dilated capillaries, and internal organ changes are absent.
Autoantibodies (ANA) may be present. RF may be present in children.
Eosinophilic fasciitis (Shulman's syndrome)
Condition may be more common in men.View image Woody induration of extremity or trunk. Peau d'orange (skin pitting like an orange peel) present. RP is unusual and there are no dilated nailbed capillaries. The limb may become worse after exercise.
Presence of serum ANA is uncommon.Peripheral eosinophilia present.Fascia biopsy shows inflammatory infiltrates including eosinophils.
Nephrogenic systemic fibrosis (NSF)
There is a history of at least one MRI with gadolinium enhancement. Cobblestone, nodular, indurated plaques of the lower extremities, trunk, feet, and hands are present. RP and dilated nailbed capillaries are absent.
Serum ANA is absent and serum creatinine is increased.
Scleroderma
Diabetes or a monoclonal gammopathy may coexist. Usually affects only the skin. Skin is indurated, doughy, and involves the neck, back, and face. RP, dilated capillaries, and internal organ involvement is absent.
Serum ANA is absent.Skin biopsy shows thickening of the dermis and hyaluronic acid between the collagen fibres.
Scleromyxoedema (or popular mucinosis)
Associated with paraproteinaemias.Affects the hands, face, and extensor surfaces. RP and dilated capillaries at the nailbeds are absent. Skin dermis can break into solid papules. Due to the deposition in the skin there can be reduced range of motion of the involved areas.
Skin deposition is mucinosis material (not collagen).
Diabetic cheiroarthropathy
Associated with diabetes mellitus. RP, nailbed dilated capillaries, skin tightness proximal to the fingers are absent. Typically both hands are affected. Limited joint mobility due to thickening of the skin and contracture of the fingers, which cannot fully extend or flatten. Rarely, larger joints are affected (generally in more advanced, long-standing diabetes).
Serum ANA is absent.
Systemic lupus erythematosus
Generalised disorder that can affect any system. Most commonly affects women during their reproductive years. Symptoms and signs may accumulate over time. RP is invariably bilateral and occurs in as many as 50% of patients at disease onset, though often predating other features of SLE.
Serum ANA is the best diagnostic test and is positive in virtually all patients with SLE.
Dermatomyositis
An idiopathic inflammatory myopathy characterised by the presence of hallmark cutaneous lesions (e.g., heliotrope rash, Gottron's papules). Skin lesions are frequently the initial presenting complaint, with muscle involvement developing later. Some patients have cutaneous involvement alone. RP may be present.
Serum CK and aldolase elevated. Skin biopsy shows perivascular or interfascicular inflammation, endothelial hyperplasia in the intramuscular blood vessels, perifascicular atrophy.
Sclerodactyly in other connective tissue diseases
Other connective tissue diseases (e.g., mixed connective tissue disease) may demonstrate sclerodactyly. Usually involves only in the distal half of the fingers.
Variable presence of anti-DNA, cytopenias, casts in the urine.

Crohn's disease

Ulcerative colitis (UC)
UC presents with features of colitis including left-sided abdominal pain and bloody diarrhoea.Does not involve small bowel or have oral or perianal disease.
Colonoscopy differentiates most cases of CD from UC. UC always involves the rectum and is contiguous versus intermittent. Terminal ileitis may be present in UC with pancolitis due to backwash. P-ANCA are positive in UC in 60% to 80% of the cases, whereas ASCA are positive in 40% to 50% of CD cases. [45] [46]
Infectious colitis
History of sick contacts and travel to endemic areas.
Stool testing reveals the infectious agent.Biopsy does not show the typical histological features of CD.
Pseudomembranous colitis
History of recent antibiotic use.Caution should be taken in differentiating the 2 conditions as Clostridium difficile infection can cause flare-up of CD.
In the proper clinical setting, a positive test for C difficile toxin is diagnostic of pseudomembranous colitis.Colonoscopy shows pseudomembranes on top of the mucosa, with no ulceration of the underlying tissue.
Ischaemic colitis
Physical findings in ischaemic colitis usually do not correlate with the severity of pain.Most patients have risk factors such as atherosclerotic diseases or hypoperfusional states (such as CHF and hypotension).
Colonoscopy shows mucosal friability in the watershed areas of the left colon.
Radiation colitis
History of exposure to external beam radiotherapy.Symptoms include abdominal pain, tenesmus, and chronic bleeding.
Colonoscopy reveals mucosal inflammation that resembles UC with friable, left-sided fibrotic and ulcerative lesions that are continuous. Many patients have bleeding angioectatic vessels.
Yersinia enterocolitica
Yersinia can cause an acute ileitis with a clinical picture resembling acute flare-up of CD.
Colonoscopic findings in Y enterocolitica enterocolitis include involvement of the terminal ileum in almost all patients and, less commonly, the ileocaecal valve, caecum, and the ascending colon. Small, rounded, or oval mucosal elevations with or without small ulcers in the terminal ileum are suggestive of Y enterocolitica enterocolitis.Stool cultures and serological tests confirm the diagnosis. [48]
Amoebiasis
Amoebiasis can mimic CD of the ileum and caecum.Recent travel to endemic areas is highly suggestive.
Stool testing for parasites.
Cytomegalovirus colitis
Immunocompromised patients, including those who have received solid organ transplant, patients on long-term immunosuppressants, or patients with HIV infection / AIDS.
Biopsy should be sent for histological examination, antigen detection, and viral culture. Classic histological findings include giant cells with cytomegaly and large ovoid or pleomorphic nuclei containing basophilic inclusions.
Colorectal cancer
Increased risk associated with increasing age and a positive FHx.
CT scan may show primary or secondary disease.Colonoscopy provides tissue for histological diagnosis.
Diverticular disease
Commonly presents with left-sided abdominal pain in patients aged 50 years and older.
CT scan shows evidence of diverticular disease with surrounding inflammation.
Acute appendicitis
Younger patients.Pain may start in the peri-umbilical area, with subsequent localisation to the right lower quadrant.
CT scan showing inflammation of appendix only.
Ectopic pregnancy
All acute presentations with abdominal pain in women of childbearing age should be considered to be due to an ectopic pregnancy until proven otherwise.May be a history of amenorrhoea, known positive pregnancy test, vaginal bleeding.
Urine and or serum beta hCG positive.Pelvic ultrasound may identify a tubal pregnancy.If rupture is suspected and the patient is haemodynamically unstable, urgent resuscitation and surgery is required.
Pelvic inflammatory disease
Vaginal discharge, dyspareunia, and pelvic pain.
Pelvic ultrasonography shows inflammatory changes in the adnexae. Rarely, laparoscopic evaluation is needed.
Endometriosis
Patients usually have cyclical symptoms starting with the menses.
Laparoscopy demonstrates the presence of endometrial tissues in the peritoneal cavity.
Irritable bowel syndrome
Chronic change in stool frequency, form, or appearance. Commonly associated with abdominal bloating and passing mucus per rectum.Spasmodic abdominal pain is often relived by defecation.CD should be suspected if symptoms are progressive or include bloody or nocturnal diarrhoea.
Screening blood tests show no evidence of inflammation.Biopsy does not show typical features of CD.Faecal calprotectin may have a future role as a screening tool; when elevated may help to distinguish a higher-risk group of patients who should be referred for endoscopic evaluation. [39]

Croup

Bacterial tracheitis
May or may not have antecedent symptoms consistent with croup; sudden deterioration following 2 to 7 days of a mild to moderate croup or other mild viral illness; [14] fever, toxic appearance (child appears unwell and does not interact normally with his/her surroundings) may be present; painful cough; poor response to treatment with nebulised epinephrine (adrenaline). [20] [21] [22] [23]
Radiological studies are contraindicated if there is clinical suspicion of bacterial tracheitis, as manipulation of the neck region and agitation may precipitate further airway obstruction.Bronchoscopy, performed at the time of intubation, shows erythematous tracheal mucosa, with thick, purulent tracheal secretions. [24]The most frequently isolated pathogens from tracheal secretions include Staphylococcus aureus, group A streptococcus, Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae, and anaerobic organisms. [14] [21] [22] [25] [26] [27]
Epiglottitis
Rarely seen since widespread immunisation against Haemophilus influenzae B; [28] [29] [30] sudden onset of high fever, dysphagia, drooling, and anxiety; preferred posture: sitting upright with head extended; non-barky cough. [14]
Radiological studies are contraindicated if there is clinical suspicion of epiglottitis, as manipulation of the neck region and agitation may precipitate further airway obstruction.Visualisation of the airway (prior to controlled endotracheal intubation) confirms the diagnosis showing an oedematous, erythematous epiglottis, often obstructing the view of the vocal cords.
Foreign body in the upper airway
Sudden onset of dyspnoea and stridor; usually a clear history of foreign body inhalation or ingestion; [14] no prodrome or symptoms of viral illness; no fever (unless secondary infection). [31]
Many foreign bodies are not radio-opaque, thus x-rays may not confirm the diagnosis.Direct visualisation and removal of foreign body in the operating room confirms the diagnosis.
Retropharyngeal abscess
Dysphagia, drooling, occasionally stridor, dyspnoea, tachypnoea, neck stiffness, unilateral cervical adenopathy; onset is typically more gradual, often accompanied by fever. [31]
Lateral neck radiograph may demonstrate retroflexion of cervical vertebrae and posterior pharyngeal oedema. [32]
Peritonsillar abscess
Dysphagia, drooling, occasionally stridor, dyspnoea, tachypnoea, neck stiffness, unilateral cervical adenopathy; onset is typically more gradual, often accompanied by fever. [31]
No differentiating tests.
Angioneurotic oedema
May present at any age; acute swelling of the upper airway may cause dyspnoea and stridor; fever uncommon. Swelling of face, tongue, or pharynx may be present.
No differentiating tests.
Allergic reaction
May present at any age; rapid onset of dysphagia, stridor, and possible cutaneous manifestations (urticarial rash); often personal or family history of prior episodes or allergy.
Allergy testing (skin prick or RAST) may determine underlying allergen
Laryngeal diphtheria
Extremely rare clinical emergency. May present at any age; history of inadequate immunisation; prodrome with symptoms of pharyngitis for 2 to 3 days; low-grade fever, voice hoarseness, potentially barky cough; dysphagia, inspiratory stridor; characteristic membranous pharyngitis on examination. [31]
No differentiating tests.
Congenital or acquired tracheal or laryngeal abnormalities
Extremely rare. Usually presents at <3 months of age.Abnormally prolonged or recurrent stridor. Poor response to croup treatment.
Upper airway endoscopy or bronchoscopy will allow direct visualisation of the underlying abnormality. However, these tests should be delayed until after the acute illness.

Cryoglobulinaemia

Small to medium vessel vasculitis
No differentiating signs/symptoms.
Vasculitis mimickers such as subacute endocarditis need to be identified urgently. Vasculitis can be life threatening, especially if there is significant multiple organ failure.Because medium-vessel vasculitis may occur due to underlying viral infections, symptoms of mesenteric ischaemia, evidence of cardiac decompensation, or hypertension should also be sought.Blood cultures, echocardiogram, HIV test, antiphospholipid antibodies, lupus anticoagulant, and other infectious-disease workup suggested by the hx (e.g., Rocky mountain spotted serologies) should be performed.A FBC, comprehensive blood chemistry profile, and urinalysis should be carried out to measure the extent of vasculitis. [4]Antineutrophil antibodies (ANCA), ANA, extractable nuclear antigen antibody (ENA), dsDNA, complement assay, eosinophil count, and specific biopsies (e.g., IgA deposits on skin or kidney suggesting Henoch-Schonlein purpura) should be ordered to establish aetiology.
Cryofibrinogenaemia
Acute unexplained areas of tissue ischaemia and gangrene; rare disorder. [32]
Cryofibrinogenaemia is a rare disorder that should be considered in any patient presenting with acute unexplained areas of tissue ischaemia and gangrene. [32] Cryoglobulins and other causes of vaso-occlusive diseases should be excluded.Cryofibrinogens are detected by cold precipitation.

Cryptococcosis

Tuberculosis
Epidemiological data showing high local prevalence of TB.As cryptococcosis is characterised by a similar latent infection with lymph node complex to that seen in TB, there are no differentiating signs or symptoms.
Sputum microscopy: presence of acid-fast bacilli.Smear culture: detection of mycobacteria using Ziehl-Neelsen stain to show acid-fast bacilli.Tuberculin skin testing with Mantoux skin test: positive result denoted by reaction of ≥15 mm of induration in populations at low risk of TB exposure or reactivation, ≥10 mm in individuals with an increased probability of recent infection or conditions (other than HIV or pharmacological immunosuppression) that increase the risk of TB, and ≥5 in the immunosuppressed. A negative test, particularly in patients with CD4 counts <300 cells/microlitre, does not rule out active or latent infection.In vitro interferon gamma release assays: high level of interferon-gamma production is indicative of TB infection.
Primary or metastatic CNS neoplasm
CNS manifestations of cryptococcosis can be mistaken for primary or metastatic neoplasms, as the signs and symptoms for both conditions are similar.The immunological state of the patient may lead to a suspicion of cryptococcosis of the CNS.
Neuroimaging: CT or MRI of the brain show presence of primary or metastatic tumour(s).Tissue biopsy: histological examination shows malignant cells.
Skin manifestations of systemic infections
Skin manifestations of cryptococcosis can mimic those of other systemic infections, including Histoplasma capsulatum, Coccidioides immitis, and Penicillium marneffei.Signs and symptoms are similar to those of cryptococcosis, but the immunological state of the patient may lead to a suspicion of cryptococcal-associated skin lesions.
Skin biopsy with culture and histology: positive for specific organism.
Opportunistic infections
AIDS patients, especially those with CD4 counts <200 cells/microlitre, are at risk of opportunistic infection with Pneumocystis jirovecii, Toxoplasma, Histoplasma, Coccidioides, Candida, Cytomegalovirus, and Mycobacterium avium complex.Signs and symptoms are similar to those of cryptococcosis.
Microscopy and culture of sputum/bronchoalveolar lavage sample: positive for specific organism.Immunofluorescent, Gomori methenamine, or Wright-Giemsa staining of sputum/bronchoalveolar lavage: positive for Pneumocystis jirovecii.

Cryptorchidism

Disorder of sex development (DSD)
Endocrine and urology referral should be made to rule out a DSD.
Karyotype and 17-hydroxyprogesterone level help distinguish between the different disorders.hCG stimulation test: no increase in testosterone, along with elevated basal levels of gonadotropins, signifies that the testes are absent.
Female with congenital adrenal hyperplasia
Occasionally, a severely androgenised female with 21-hydroxylase (the most common) congenital adrenal hyperplasia may present with a phallic structure and presumed bilateral undescended testicles, and may have life-threatening metabolic disturbances.
Elevated serum17-hydroxyprogesterone and serum testosterone.

Cryptosporidiosis

Acute diarrhoea
Any infectious agent (bacterial, viral, parasitic) causing gastroenteritis may cause a similar presentation.
Stool culture and microscopy or serological tests for bacterial pathogens, other parasites, or gastrointestinal viruses positive according to pathogen.
Chronic diarrhoea
Any infectious agent causing gastroenteritis may cause a similar presentation, but in chronic diarrhoea there may be other contributing non-infectious factors such as intestinal disorders, infiltrative diseases, and iatrogenic causes.
Stool culture and microscopy or serological tests for bacterial pathogens, other parasites, or gastrointestinal viruses positive according to pathogen.
Crohn's disease
May present with fatigue, diarrhoea, abdominal pain, weight loss, fever, and rectal bleeding. Other signs may include oral ulcers, perianal skin tags, fistulae, abscesses, and sinus tracts; no mass present on digital rectal examination.
Stool culture, microscopy, and antigen testing: negative.Upper GI and small-bowel series: oedema and ulceration of the mucosa with luminal narrowing and strictures.CT/MRI abdomen: skip lesions, bowel-wall thickening, surrounding inflammation, abscess, fistulae.Colonoscopy: aphthous ulcers, hyperaemia, oedema, cobblestoning, skip lesions.
Ulcerative colitis
May present with bloody diarrhoea, history of lower abdominal pain, faecal urgency, presence of extra-intestinal manifestations (e.g., erythema nodosum, acute arthropathy), history of primary sclerosing cholangitis; no mass present on digital rectal examination.
Stool culture, microscopy, and antigen testing: negative.Histology: continuous distal disease, mucin depletion, basal plasmacytosis, diffuse mucosal atrophy, absence of granulomata, and anal sparing.Colonoscopy: rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas (rarely seen), normal terminal ileum (or mild 'backwash' ileitis in pancolitis).
Gut acute graft-vs-host disease (aGVHD)
Profuse diarrhoea following bone marrow transplant may be a sign of gut aGVHD.
Exclude presence of Cryptosporidium; stool and antigen testing negative for other infectious agents; histological evidence of aGVHD on endoscopic biopsy.

Cushing's syndrome

Obesity
Usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures. [25]
Normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol.
Metabolic syndrome
Usually lack facial plethora, unexplained bruising, proximal muscle weakness, violaceous striae, supraclavicular fullness, and osteoporotic fractures. [25]
Normal late-night salivary cortisol, dexamethasone suppression testing, or 24-hour urinary free cortisol.

Cutaneous burns

Rash in children
No accident in the history.
No specific test.

Cutaneous larva migrans

Larva currens
Caused by Strongyloides infection. Lesions typically found in perianal area, abdomen, and upper thighs, and last for only a few hours; characterised by a single track that advances rapidly by several centimetres an hour. [27]
Strongyloides larvae seen on microscopic stool examination; positive Strongyloides IgG serology.
Gnathostomiasis
Caused by Gnathostoma spinigerum. Usually a history of eating raw or undercooked fish. Presents with a migratory swelling or subcutaneous nodule.
Positive serological tests.Surgical excision of the lesion may reveal the nematode larvae.
Fascioliasis
Caused by Fasciola gigantica. History of eating raw leafy vegetables in Asia or Africa. Cutaneous track is deeply erythematous and tunnel-like. [28] Lesions cause burning pain and extend by 4 to 5 cm per day.
Positive serological tests.Extraction of fluke from advancing end of track.
Spirurina species infection
Cases reported only in Japan. [29] Associated with eating raw seafood. Creeping eruption identical to CLM but usually single lesion present on abdomen.
Positive serological tests.
Myiasis
Characterised by cutaneous nodules often with central punctum. Patient frequently aware of movement within nodule. May migrate but typically no thin serpiginous track present. Lesions are not usually located on the feet.
Extraction of fly maggot from skin lesion.
Loiasis
History of exposure to mosquitoes in Central and West Africa. Swelling is subcutaneous. Adult worms may migrate across conjunctivae.
Identification of microfilariae on microscopic examination of blood sample; positive serological tests.
Creeping hair
No association with travel. Typically involves slowly migrating skin fragment in upper dermis. Pruritus not pronounced.
Extraction of hair from advancing end of skin lesion.
Scabies
Pruritus typically worse at night. In addition to papules or vesicles, burrows may be evident and will help to make the diagnosis. The wrists, ankles, palms, soles, interdigital spaces, axilla, waist, and groin are the most commonly affected sites. Patients will often report similar symptoms in family members or other close contacts. [30]
Microscopy of skin scrapings may reveal mites, eggs, or scybala (mite faeces).
Cercarial dermatitis (schistosomiasis)
Usually diffuse maculopapular rash. Skin lesions are non-migratory. [31] Rash typically appears within 24 hours of fresh-water contact in endemic area (Africa, China, the Philippines, Brazil, and other tropical countries in South America and the Caribbean).
Diagnosis is initially clinical because egg laying has not yet begun; later, microscopy of stool and urine allows quantification of egg burden and Schistosoma species identification, and schistosomiasis serology will reveal antibodies against parasite antigens.
Herpes zoster infection
Typical dermatomal distribution. Skin lesions are non-migratory and are characterised by vesicles that may coalesce and then crust. Usually more painful than pruritic.
Smears of vesicle scrapings stain positive for varicella virus.
Jellyfish sting
Association with swimming in the ocean. Skin lesions are non-migratory.
Diagnosis is clinical.
Phytophotodermatitis
Skin lesions are typically non-migratory and non-pruritic. In addition, they are usually pleomorphic and not just narrow serpiginous tracks. [32]
Diagnosis is clinical.
Superficial thrombophlebitis
Skin lesions are not usually migratory. Associated with pain and erythema but not pruritus. Clotted superficial vein usually palpable as a tender cord.
Duplex ultrasound demonstrates lack of compressibility or intraluminal thrombus in the superficial veins.

Cutaneous T-cell lymphoma

Psoriasis
A common inflammatory dermatosis. Typically presents with well-defined erythematous plaques with silvery scales that are symmetrically distributed and favour extensor surfaces of elbows, knees, View image lower back, and scalp. May also present with guttate, pustular, and erythrodermic lesions. Nails and joints may be involved.Typically diagnosed on clinical features alone. Family history of psoriasis common.
Histology on skin biopsy specimen shows epidermal acanthosis, parakeratosis, absence of granular layer, and neutrophil micro-abscesses with dermal vascular dilatation.
Eczema
A heterogeneous group of inflammatory dermatoses characterised by intensely itchy, erythematous papulovesicles, patches, and thickened lichenified plaques. In the most common variant, atopic eczema, these are symmetrically distributed and favour flexural surfaces of elbows, knees, hands, and face. Weeping, crusting, excoriation, and signs of secondary infection are frequently present. May present with erythrodermic eczema. Other clinical variants include irritant and allergic contact eczema, discoid (nummular) eczema, pompholyx eczema, and photosensitive eczema.Typically diagnosed on clinical features alone. Positive FHx is usually present in atopic eczema and associated with other atopic manifestations, such as asthma and hay fever. Pruritus is usually the predominant symptom.
Histology depends on eczema subtype, but typically shows spongiosis of the epidermis with a mixed inflammatory cell infiltrate and secondary epidermal changes due to scratching.
Dermatophyte infection
Common infectious dermatosis of skin, scalp, and nails. Typically affects web spaces of toes (athlete's foot) and groins (jock itch). When it affects other body sites, typically presents with asymmetrical, erythematous, annular lesions, with scaling at the leading edges of lesions. Topical corticosteroids may induce pustular changes and lead to deterioration.
Diagnosis confirmed by microscopy (KOH preparation) and culture of skin scrapings. If skin biopsy taken, no evidence of atypical lymphocytes in epidermis. Periodic acid-Schiff (PAS) stain positive.
Parapsoriasis
A group of inflammatory skin conditions characterised by scaly patches or slightly elevated papules and/or plaques that resemble those of psoriasis. There is no uniformly accepted definition, but the group generally includes small-plaque parapsoriasis (digitate dermatoses, chronic superficial dermatoses), a benign condition, and large-plaque parapsoriasis, which may be a precursor of CTCL in a proportion of cases.Pityriasis lichenoides (acuta and chronica), a benign lymphoproliferative disorder of unknown cause, is sometimes included in this category.
No specific diagnostic finding on histology to define parapsoriasis, which is a clinico-pathological correlation.

Cystic fibrosis

Primary ciliary dyskinesia
Usually not associated with pancreatic insufficiency; chronic purulent middle ear infections, which are less common in children with CF
Ciliary biopsy will demonstrate ultrastructural abnormalities of respiratory cilia.
Primary immunodeficiency
Severe combination of immune deficiency with respiratory infections, IgA deficiency, and IgG1 deficiency; may be associated with non-respiratory infections. Usually not associated with pancreatic insufficiency.
Measurement of lymphocyte number and function, neutrophil function, and immunoglobulin levels.
Asthma
Usually not associated with purulent bronchitis. Patients with asthma usually will not demonstrate digital clubbing.
There is no diagnostic test. Diagnosis is made clinically. Some children with CF also present with asthma.
Gastro-oesophageal reflux disease (GORD)
Usually not associated with signs or symptoms of malabsorption.
Modified barium swallow or gastric emptying studies may be useful in making the diagnosis of chronic aspiration or GORD, but may also be positive in patients with CF.
Chronic aspiration
Usually not associated with signs or symptoms of malabsorption.
Modified barium swallow or gastric emptying studies may be useful in making the diagnosis of chronic aspiration or GERD, but may also be positive in patients with CF.
Failure to thrive
May not be associated with respiratory symptoms.
Sweat test should be negative if CF is not the cause. However, severe malnutrition causes a falsely elevated sweat test.
Coeliac disease
Patients with coeliac disease will respond to removal of gluten from the diet.
Intestinal biopsies.
Protein-losing enteropathy
Loss of serum protein through the GI tract. Can be associated with Fontan's procedure, lymphatic disorders, or mucosal erosion.
Intestinal biopsies.

Cytomegalovirus infection

Infectious mononucleosis
The clinical presentation of infectious mononucleosis syndrome is most commonly caused by Epstein-Barr virus (EBV) infection, and is clinically indistinguishable from CMV.
EBV PCR assay; EBV serology
HIV
Acute HIV seroconversion often manifests with a febrile syndrome that may be difficult to distinguish from primary CMV disease.This syndrome may include fever, chills, and generalised lymphadenopathy.
HIV serology; HIV RNA level
Human herpes virus (HHV)-6
HHV-6 infection after transplantation may manifest in a clinically similar way to CMV disease, and can be distinguished only by the detection of HHV-6-specific antigens or nucleic acid in clinical specimens.
HHV-6 PCR assay
Other viral illness
Viral infections often present as fever in immunocompromised patients and thus may be indistinguishable from CMV.
Virus-specific culture and PCR assays

Deep vein thrombosis

Cellulitis
Patients with cellulitis usually manifest redness, heat, and swelling in the dermis of the affected leg, with rather poorly defined margins to the affected skin.Portal of infection entry may be identified. [51]Fever and prior history of cellulitis is common.May occur concomitantly with a recurrent DVT.
Leukocytosis is common, with a WBC count >10.0 X 10^9/L (10,000 cells/microL).
Calf muscle tear
History of trauma or sudden onset of calf pain.Defect or spasm of calf muscles noted on examination.
No DVT is seen on venous ultrasound, but defect or spasm of calf muscles noted.
Calf muscle haematoma
Calf injury or sudden onset of calf pain.
Venous ultrasound shows no thrombosis. There may be evidence of a haematoma in the calf.
Popliteal cyst (Baker's cyst) compressing the popliteal vein
Non-tender bulge in popliteal fossa. There is usually moderate or large knee effusion.
Venous ultrasound shows large fluid-filled bursa behind the knee with no evidence of DVT.
Pelvic/thigh mass/tumour compressing venous outflow from the leg
Recent catheterisation of the femoral artery in the groin can cause pseudoaneurysm of femoral artery or pelvic haematoma.
Venous ultrasound, and CT scan of abdomen, pelvis, and thigh with contrast, may show obstructing mass impinging on the femoral, iliac, or vena cava vessels.

Degenerative cervical spine disease

Whiplash injury (cervical myofascial strain)
Caused by acceleration/deceleration injuries to the neck, most commonly from rear-end automobile accidents. Approximately 65% of patients make a full recovery, 25% have minor residual symptoms, and 5% to 10% develop chronic pain syndromes. Broad spectrum of symptoms, including neck stiffness, shoulder or arm pain, myalgias, paraesthesias, headache, facial pain, and vertigo.
Plain x-rays usually ordered to rule out fracture or subluxation due to a ligament tear. X-rays sometimes reveal a straightening of the natural curve in the neck because of extensive muscle spasm. Most patients will have normal radiological studies. If disc herniation or nerve root compromise is suggested, an MRI study can help pinpoint the problem. [5]
Acute disc herniation
History of repetitive cervical stress or, rarely, from a single traumatic incident. Increased risk may accrue because of vibrational stress, heavy lifting, prolonged sedentary position, whiplash accidents, and frequent acceleration/deceleration.Cervical radiculopathy can result from nerve root injury in the presence of disc herniation or stenosis, most commonly foraminal stenosis, leading to sensory, motor, or reflex abnormalities in the affected nerve root distribution.
Best diagnosed by an MRI scan. If >1 level of herniation appears, a CT myelogram can help distinguish which disc is irritating the spinal nerve.If radiculopathy symptoms are present, an EMG can reveal which nerve is affected, but does not confirm disc herniation. EMG is most effective when the MRI shows >1 level of herniation and there is no definite motor, sensory, or reflex deficit, to distinguish which nerve root is affected.
Metastatic malignancy
Spontaneous but severe, persistent pain, particularly with boney involvement, which does not resolve with initial treatments.Bone invasion is common in known malignancy, but can often be the initial sign of an advanced, undiagnosed malignancy.
Cervical MRI showing mass lesion of bone or soft tissue or multiple lesions suggestive of boney metastases.
Multiple myeloma
Most common tumour to the spine (along with plasmacytoma). Latter is rare, implies a single lesion with an indolent clinical course and is seen more commonly in a young person. Multiple myeloma is seen in older patients, is rapidly progressive, and commonly presents with neurological symptoms due to vertebral body collapse. Patients may also have symptoms associated with hypercalcaemia and renal failure.
X-rays of the cervical spine show ≥1 lytic vertebral bodies.Multiple myeloma is a plasma cell dyscrasia characterised by infiltration of the bone marrow by plasma cells, and the presence of a monoclonal immunoglobulin or immunoglobulin fragment in the serum and/or urine.Bone marrow aspirate and biopsy with histopathology shows atypical plasma cell infiltrates.
Osteomyelitis or discitis
More severe, spontaneous neck pain, often following systemic infection, with marked decreased range of motion, or with progressive neurological changes in upper extremities. Commonly begins as a cervical discitis (i.e., disc space infection) because the disc is highly susceptible to infection. Spreads to adjacent bone, with severe neck pain. Often this entity follows sepsis at some interval, so patient may be over their septic episode by the time the actual neck pain begins.
Cervical MRI usually shows evidence of bone or disc space infection. Infected areas typically appear with decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images.
Epidural abscess
Commonly an extension of discitis through spinal venous spread, leading to severe neck pain. In advanced cases, leads to compressive myelopathy from spinal cord compression.
Cervical MRI is the preferred test, because both the epidural collection and its effect on the spinal cord are easily discernible, as well as the likely source of the infection. MRI with contrast helps to indicate the spread of the infection.
Cervical bone or joint instability
More severe spontaneous neck pain or progressive loss of neurological function.Presence of underlying medical conditions such as rheumatoid arthritis (i.e., C1/2), previous trauma, previous surgery, congenital abnormality (skull base), or spontaneous degenerative spondylolisthesis.
Cervical radiographs together with cervical MRI helpful to distinguish presence of instability, levels involved, and features of associated condition.
Fibromyalgia
Presents with widespread body pain persisting for >3 months with multiple tender points; somatic complaints include chronic headaches, sleep disturbance, depression and anxiety, irritable bowel syndrome, genitourinary disturbances, and diffuse sensory disturbances.
No radiographic or laboratory test; the diagnosis is strictly clinical. However, if the patient does not meet clinical criteria for a diagnosis, tests including FBC, TFT, RF, and ANA may help explain the patient's musculoskeletal pain or fatigue.
Polymyalgia rheumatica (PMR)
Presents with history of neck, shoulder girdle, and/or hip girdle stiffness and pain, occurring in patients aged >50 years (usually women). Patients complain of difficulty rising from seated or prone positions, varying degrees of muscle tenderness, shoulder/hip bursitis, and/or oligoarthritis.Rapid improvement is almost invariable within 24 to 48 hours with low-dose prednisolone.
Diagnosis is made by history and with supportive laboratory tests indicating an elevated ESR or C-reactive protein.Diagnostic and therapeutic corticosteroid trial.
Giant cell arteritis (GCA) or temporal arteritis
Associations are new-onset unilateral headache, jaw claudication associated with chewing tough foods, diffuse mandibular discomfort, dental discomfort, sinus pain and pressure, and/or tongue pain. Blindness, diplopia or blurry vision, and an abnormally thickened, tender, erythematous, or nodular temporal artery are also found.Patients aged >50 years with new-onset headache should be screened for GCA or temporal arteritis. About 15% to 20% of patients with PMR have GCA; 40% to 60% of GCA patients have PMR.
Elevated ESR or CRP.A positive temporal artery biopsy showing a granulomatous vasculitis confirms the diagnosis of GCA.Diagnostic and therapeutic corticosteroid trial.
Ankylosing spondylitis
A chronic progressive inflammatory arthropathy predominantly affecting the axial spine and sacroiliac joints. Patients present with severe pain and spinal stiffness, which may ultimately lead to spinal fusion (bamboo spine). These patients have extreme disability as a consequence. Peripheral joints, entheses (tendon or ligament attachments to bone), and extra-articular sites such as the eye and bowel are frequently affected.
There is no diagnostic test. HLA-B27, although not diagnostic, is helpful if it is positive. Inflammatory markers such as ESR and CRP are generally unhelpful in diagnosing or monitoring. Radiographs of the cervical spine may show spinal fusion (bamboo spine).
Rheumatoid arthritis (RA)
Pain and/or swelling in several joints, significant joint stiffness in the morning or after rest, progressive loss of joint function, symmetrical joint involvement, and good response to NSAIDs, with most patients presenting in their 50s.Less-common extra-articular features such as rheumatoid nodules over the extensor surfaces of tendons or vasculitic skin involvement may be seen. Clinical signs seen in more severe presentations include pleuritis, pericarditis, and inflammatory eye disease.
Baseline radiographs of the hands and feet and spine show erosion of cartilage.RF is positive in about 70% of patients with RA. Anti-cyclic citrullinated peptide antibodies (anti-CCP) are newly described and are found in about 70% to 80% of patients with RA. They can be positive when RF is negative and seem to play more of a pathogenic role in the development of RA.ESR or CRP levels are usually obtained to reflect the level of inflammation. However, up to 40% of patients with RA may have normal levels.
Cluster headache/chronic headache syndromes
Diagnosed from the clinical history. The most important historical factors are frequency of headaches, duration of attacks, severity of attacks, whether the headache is constant or intermittent, or unilateral or bilateral, associations (nausea, sensitivity to light or noise), and presence of trigger factors or associations with injury or analgesic overuse.Headache episodes lasting <2 hours are in keeping with chronic cluster headaches. Episodes lasting >2 hours would be in keeping with either migraine or tension-type headaches.
Is a clinical diagnosis of exclusion.Cervical myelogram, CT scan, or MRI will be negative for cervical disc disease or spinal cord disease.
Osteoporosis
Common in postmenopausal women or older men with maternal history of fragility fractures/osteoporosis, low BMI, and tobacco use. Patients with osteoporosis are asymptomatic until fracture occurs.
Measurement of BMD using DXA is the definitive test and preferred procedure diagnosis. Use of DXA for screening patients with risk factors will diagnose many cases of osteoporosis.X-ray can reveal osteopenia and/or fractures (e.g., vertebral fractures), but is not diagnostic of condition.Quantitative CT or quantitative ultrasound of the heel can be used to measure trabecular bone density if DXA is unavailable.
Spinal compression fracture
Usually a history of trauma, although the acute event is not always recalled; pain at rest and at night; previous history of fractures; tenderness to palpation over the midline; increased kyphosis; normal neurological examination unless there is retropulsion of bone into the neural elements, such as in burst fractures.
Plain radiograph shows wedging of the vertebral bodies, typically anteriorly; kyphotic deformity; only the anterior half of the vertebral body is involved in compression fractures.
Polymyositis
History of symmetrical weakness of shoulder and pelvic girdles.
Elevated muscle enzyme levels (e.g., CK) often with a positive ANA titre.Characteristic changes in EMG include increased needle insertional activity, spontaneous fibrillations, low-amplitude short-duration polyphasic motor potentials, and complex repetitive discharges.Diagnosis is confirmed with muscle biopsy, indicating immune cell infiltration and destruction of muscle fibres.
Thoracic outlet syndrome
Intermittent unilateral or bilateral upper extremity numbness, often with no objective sensory loss, and weakness noted rarely. Cervical myelopathy is constant, with both upper and lower extremity neurological changes often noted.Caused by compression of the neurovascular structures just above the first rib and behind the clavicle, involving the lower 2 nerve roots of the brachial plexus (C8 and T1). Less commonly, C5, C6, and C7 involvement leads to symptoms referred to the neck, ear, chest, and outer arm.
Brachial angiograms may show vascular stenosis and EMG/nerve conduction velocity (NCV) may show proximal brachial plexus changes consistent with thoracic outlet.Cervical radiology may demonstrate a skeletal abnormality, cervical or first rib, clavicle deformity, pulmonary disease, or Pancoast tumour.Colour-flow duplex scanning, arteriography, or venography of the arm may demonstrate vascular thoracic outlet syndrome.Cervical myelogram, CT scan, or MRI will be negative for cervical disc disease or spinal cord disease.
Brachial plexus injury
Unilateral severe proximal and distal weakness and sensory loss, often following injury, or spontaneous (neuralgic amyotrophy) following viral infection, in a different pattern from cervical radiculopathy or myelopathy.
EMG/NCV can easily differentiate lower versus upper motor neuron changes.MRI or cervical myelogram may show root avulsion changes.
Multiple sclerosis
Spinal manifestations can mimic all signs of cervical compressive myelopathy and overlap. However, in almost all cases there are also brain lesions and neurological findings.
Brain MRI typically shows changes. On cervical MRI there is no compression but intrinsic spinal cord lesions are usually noted.
Mononeuritis multiplex (MNM)
Distinctive clinical presentation of progressive motor and sensory deficits in the distribution of specific peripheral nerves.Involvement of each nerve occurs either sequentially or simultaneously.Pain is a frequent symptom; usually neuropathic pain within the area of sensory loss and deep pain in the affected extremity.
Diagnosis is based on clinical picture and characteristic vasculitic changes seen on nerve or muscle biopsy without demyelination.EMG can distinguish MNM caused by vasculitis, infection, or neoplastic infiltration from multiple entrapment neuropathies.Cervical myelogram, CT scan, or MRI will be negative for cervical disc disease or spinal cord disease.
Amyotrophic lateral sclerosis
Can mimic cervical myelopathy, but typically has more severe proximal weakness, fasiculations, brainstem findings (i.e., tongue fasiculations), and no sensory changes.
Cervical MRI does not show any significant spinal cord compression but may show intrinsic spinal cord lesions.
Complex regional pain syndrome
Severe, diffuse upper extremity pain (usually unilateral) in a non-radicular distribution, typically following an injury or a surgical procedure on that upper extremity. There are no specific sensory or motor changes beyond limitation by pain.
Cervical MRI and typically EMG/NCV will both be normal. Sympathetic blocks may help differentiate.
Hereditary muscular dystrophy
Severe proximal and distal weakness without sensory changes from an early age.
Cervical MRI and EMG/NCV will show only myopathic changes and no spinal cord compression.

Delayed puberty

Premature ovarian failure
Females may have had normal pubertal development or pubertal arrest.Present with primary or secondary amenorrhoea.
Ovarian antibodies may be positive.
Premature testicular failure
Males may have had normal pubertal development or present with pubertal arrest.Present with decreased libido, features of testosterone deficiency, and/or infertility.
No differentiating tests.
Hypothyroidism
Pathophysiology of delayed puberty not known.Up to half of patients have no or non-specific symptoms.Common symptoms include weakness, lethargy, slow speech, cold sensation, forgetfulness, constipation, and weight gain.On examination, patients have coarse, dry skin and bradycardia.Unless symptoms are long-standing, patients generally have some pubertal development; females report menstrual irregularities.
TSH levels are elevated in primary hypothyroidism; free T4 levels are decreased.
Polycystic ovary syndrome
Females present with obesity, hirsutism, acne, oily skin, and weight gain.May have normal pubertal development, but anovulatory cycles may lead to absent menarche.On examination, there may be acanthosis nigricans, obesity, and increased waist-hip ratio.
Pelvic ultrasound reveals polycystic ovaries with variable endometrial thickness.Measurement of serum androgens reveals elevated dehydroepiandrosterone sulphate (DHEAS) and testosterone.Fasting glucose and insulin are elevated due to insulin resistance.
Outflow tract obstruction, including imperforate hymen or transverse vaginal septum
Normal pubertal development but cyclic pelvic pain and lack of menarche.On examination, girls have either a perirectal mass or a bulging hymen with haematocolpos.
Pelvic ultrasound reveals variable abnormalities, such as imperforate hymen, blood within the vagina, or thickened tissue within the vagina. The uterus and ovaries are normal.
Mayer-Rokitansky-Kuster-Hauser syndrome
Mullerian agenesis syndrome.Normal-onset pubertal development except menarche.Phenotypically female external genitalia with blind vaginal pouch.
Pelvic ultrasound reveals variable absence of Mullerian structures.
Complete androgen insensitivity
Phenotypically female with normal timing of breast development, minimal to no pubic hair growth, and no menarche.On examination, females have an absent or blind vaginal pouch and a palpable inguinal mass (testes).
Chromosomal analysis reveals a 46XY male in a phenotypic female.Pelvic ultrasound reveals the presence of testes with no ovaries or uterus.
5-Alpha-reductase deficiency
Boys present with poor virilisation at puberty, although the vast majority have genital ambiguity on examination.
Testosterone: dihydrotestosterone ratio is markedly elevated.
Cushing's syndrome
May present with oligomenorrhoea in females; pubertal development is normal.Additionally, patients have central obesity with thin extremities, nuchal fat pad, moon facies, purple striae, bruiseability, and hirsutism in females.
24-hour urinary free cortisol and morning (8 a.m.) serum cortisol are elevated.

Depression

Situational adjustment reaction with depressed mood
This is a subsyndromal depression with a clearly identified precipitating event. It usually does not require medicine and resolves with resolution of the acute stressor.
DSM-IV-TR.
Bipolar disorder
In this condition, major depressive disorder is accompanied by or interspersed with one or more manic or mixed episodes.
DSM-IV-TR.
Premenstrual dysphoric disorder (PMDD)
PMDD is characterised by depressed mood, anxiety, and irritability during the week before menses and resolving with menses. PMDD also has prominent pain symptoms.
DSM-IV-TR.
Grief reaction
The syndrome of major depression may be transiently present in normal grief. The duration and expression of normal grief varies among racial/ethnic groups. [33]Symptoms more consistent with depression include inappropriate guilt regarding actions surrounding death of loved one, persistent thoughts of death (survivor's feelings that he or she would be better off dead or should have died with the deceased person are considered a normal part of grief), morbid preoccupation with worthlessness, marked psychomotor retardation, prolonged and marked functional impairment, and hallucinations. Transiently hearing the voice of or seeing the deceased person is considered within normal limits of bereavement.Patients with unremitting symptoms after 4 to 6 months should be assessed for depression.
DSM-IV-TR.
Dementia
Dementia is characterised by cognitive (memory) changes, psychiatric symptoms, personality changes, problem behaviours, and changes in day-to-day functioning.
A mini-mental state examination (MMSE) [34] or neuropsychiatric testing should be conducted if the diagnosis is uncertain.Focused laboratory testing (i.e., TSH level, vitamin B12 level) should be considered for reversible causes of dementia.
Anxiety disorders
Anxiety disorders frequently occur along with depression. Generalised anxiety disorder is characterised by excessive worry, muscular tension, fatigue, autonomic hyperactivity, and increased vigilance. Specific anxiety disorders (i.e., panic disorder, social phobia, OCD, PTSD) should also be considered.
DSM-IV-TR.
Alcohol abuse
Patients often may complain of insomnia, nightmares, poor memory, and nervousness.
The CAGE questionnaire has 4 questions:C: have you ever felt you should cut down on your drinking?A: have people annoyed you by criticising your drinking?G: have you ever felt bad or guilty about your drinking?E: have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye opener)?Item responses are scored 0 or 1, with a higher score indicating an alcohol problem. A total score of ≥2 is considered clinically significant. [35]
Anorexia nervosa
Eating disorders such as anorexia nervosa are more common in women and characterised by disturbance in the perception of body weight, size, or shape, and refusal to maintain healthy body weight.
DSM-IV-TR.
Hypothyroidism
Associated signs and symptoms include weight gain, constipation, and fatigue.
An elevated serum TSH level suggests hypothyroidism.
Medicine adverse effects
Patient should be asked about use of glucocorticoids, interferon, levodopa, propranolol, and oral contraceptives. The data regarding isotretinoin remain unclear. [36]
These effects may be temporally associated with medicine initiation.
Cushing's disease
This disease is associated with progressive obesity, dermatological manifestations, signs of adrenal androgen excess, and proximal muscle wasting.
Elevated 24-hour urinary free cortisol level.
Vitamin B12 deficiency
This deficiency is associated with macrocytic anaemia, paraesthesia, numbness, and impaired memory.
Reduced serum vitamin B12 level.

Depression in children

Bipolar disorder
Clinical examination using the DSM-IV-TR criteria establishes differentiating symptoms and signs.Elevated mood, decreased need for sleep, inflated self-esteem or grandiosity, increased goal-directed activities, racing thoughts, pressured speech, and reckless pleasurable behaviour are all characteristics of hypomanic or manic episodes of a bipolar illness. A child, particularly an adolescent, who presents with a history or concurrent manic or hypomanic symptoms needs to be assessed carefully to exclude the possibility of a bipolar illness.
No differentiating test.
Anxiety disorder
Clinical examination using the DSM-IV-TR criteria establishes differentiating symptoms and signs.Anxiety disorders that meet diagnostic criteria will usually precede depressive symptoms. Anxiety disorders do not occur exclusively during a mood disorder; rather, symptoms of anxiety are present even in the absence of mood symptoms.However, anxiety disorders are highly co-morbid with depressive disorders, and assessment and management of both disorders will improve outcome.
No differentiating test.
ADHD
Clinical examination using the DSM-IV-TR criteria establishes differentiating symptoms and signs.ADHD is diagnosed when full diagnostic criteria are met prior to age 7 years. In patients with ADHD only, poor concentration is a chronic symptom that precedes depressive symptoms. ADHD, however, is highly co-morbid with depressive disorders, and assessment and management of both disorders will improve outcome.
No differentiating test.
Substance abuse
Clinical examination using the DSM-IV-TR criteria helps to establish differentiating symptoms and signs.Substance abuse may precede depressive symptoms or occur as a consequence of depression.
Urine drug screen confirms concomitant use of substance.
Adjustment disorder with depressed mood
A stressor always precedes the depressive symptoms.In addition, the depressive symptoms should not meet full DSM-IV-TR criteria for major depressive disorder.
No differentiating test.
Bereavement
A recent loss of a loved one always precedes the depressive symptoms.In addition, the depressive symptoms should not meet full DSM-IV-TR criteria for major depressive disorder or persist >2 months.
No differentiating test.
Acute stress disorder
A recent exposure to a traumatic event, by experiencing, witnessing, or confronting, which causes intense fear, helplessness, or horror.In addition, a child has dissociative symptoms, re-experiencing of the trauma, avoidance behaviour, and increased anxiety or arousal.
No differentiating test.
Post-traumatic stress disorder
Exposure to a traumatic event, by experiencing, witnessing, or confronting, which causes intense fear, helplessness, or horror for at least 1 month after the event.In addition, the child has dissociative symptoms, re-experiencing of the trauma, avoidance behaviour, and increased anxiety or arousal.
No differentiating test.
Oppositional defiant disorder
Clinical examination using the DSM-IV-TR criteria helps to establish differentiating symptoms and signs.Behavioural problems are more chronic and present without concurrent mood symptoms.
No differentiating test.
Anorexia nervosa
Clinical examination using the DSM-IV-TR criteria helps to establish differentiating symptoms and signs.Additional symptoms, such as body image distortions and fear of gaining weight, occur without mood symptoms.However, eating disorders and depression can be co-morbid.
No differentiating test.
Bulimia nervosa
Clinical examination using the DSM-IV-TR criteria helps to establish differentiating symptoms and signs.Additional symptoms, such as body image distortions and over-eating, occur without mood symptoms.However, eating disorders and depression can be co-morbid.
No differentiating test.
Thyroid dysfunction
Hypothyroidism may be associated with weight gain and constipation. On examination there may be dry, coarse skin, goitre, bradycardia, facial puffiness, slow return of deep tendon reflexes, or tongue thickening.Hyperthyroidism may be associated with weight loss, increased appetite, sweating, and nervousness. On exam there may be goitre, rapid return of deep tendon reflexes, or tremor.
In primary hypothyroidism, TSH is elevated and free T4 is low.In central hypothyroidism, TSH is inappropriately low or normal for the free T4 level, and free T4 is low.In hyperthyroidism, TSH is suppressed and serum free T4 and/or T3 are elevated.
Anaemia
May be associated with a history of poor nutrition, pallor, and prominent fatigue.
FBC reveals low Hb.
Infectious mononucleosis
History of initial symptoms of fever, fatigue, malaise, pharyngitis, and cervical or generalised lymphadenopathy.
Positive agglutination test (e.g., monospot) showing heterophile antibodies.Serological test demonstrating EBV-specific antibodies.FBC with differential may demonstrate lymphocytosis, atypical lymphocytosis, anaemia, and reticulocytosis.
Vitamin deficiency
May be associated with a history of poor nutrition, pallor, and prominent fatigue.
FBC may reveal anaemia.Blood levels of vitamins may be low. However, tests would only usually be performed if vitamin deficiency were considered a likely cause of symptoms.Further specific tests of vitamin deficiency may be used to confirm deficiency.
Temporal lobe epilepsy
History of recurrent and chronic focal seizures.
EEG reveals spikes or sharp waves in the temporal lobe area. This would only usually be performed if temporal lobe epilepsy were considered a likely cause of symptoms.

Dermatomyositis

Subacute cutaneous lupus erythematosus (SCLE)
Lesions generally occur between the knuckles, whereas in dermatomyositis (DM) they tend to occur over bony prominences.Pruritus is usually absent. [66]
Autoantibodies: anti-Mi-2 positive in 25% of DM patients. Anti-Ro (SS-A) antibody positive in 60% to 70% of patients with SCLE. [66]Skin biopsy: histology of DM and SCLE are often indistinguishable. Immunofluorescent microscopy should be negative in DM and positive in SCLE, but positive microscopy is found in only 50% of SCLE cases and false positives may occur on sun-exposed DM skin. [66]
Psoriasis
Scalp lesions tend to be patchy rather than diffuse.Not photo-aggravated and often improves with sun exposure.Presence of psoriatic nail lesions.Pruritus is less common.
Skin biopsy shows intra-epidermal spongiform pustules and Munro's neutrophilic micro-abscesses within the stratum corneum.
Cutaneous T-cell lymphoma
Cutaneous lesions are not photodistributed. They are also found on non-sun-exposed skin. [60]
Skin biopsy has distinct pathological findings that distinguish the lesions from those of dermatomyositis.
Scleroderma
Presence of skin thickening and sclerosis. Erythema is not a prominent feature.Raynaud's phenomenon is a prominent and often severe symptom in systemic sclerosis that predates the onset of skin involvement, often by several years.
Anti-centromere antibodies are present in 50% to 90% of patients with limited systemic sclerosis.Anti-Scl-70 antibodies are present in 20% to 30% of patients with systemic sclerosis and are associated with the diffuse variant. [9]Anti-PM-Scl antibodies have been found in patients with overlapping myositis and scleroderma. [107]Skin biopsy has distinct pathological findings that distinguish the condition from DM.
Trichinosis
Muscle pain, peri-orbital oedema, and macular or urticarial rashes.
Serology: antibodies against the trichinella parasite can be measured 2 to 3 weeks after infection.Muscle biopsy: identifying larvae in muscle tissue makes the definitive diagnosis. [114]
Drug-induced DM-like reactions
History of medicine associated with development of skin lesions indistinguishable from DM (e.g., hydroxyurea).The eruption resolves with withdrawal of the drug but make take up to 18 months. Patients may have residual scarring and skin atrophy. [27]
Investigations for muscle involvement are typically negative.
Overlap myositis
Symptoms of DM associated with some other connective tissue disorders.Diagnostic criteria for the 2 different disorders are fulfilled.
Additional serological features diagnostic of an underlying connective tissue disease (e.g., SLE, rheumatoid arthritis, scleroderma, or mixed connective tissue disease).

Dermatophyte infections

Atopic dermatitis
History of atopy and lack of lesions with active inflammatory border with central clearing. Lesions in flexural folds of neck, arms, and legs. Chronic and relapsing, often since childhood.
Diagnosis is clinical. Potassium hydroxide (KOH) microscopy is infrequently done, and rarely fungal culture or biopsy may be undertaken to exclude diagnosis of dermatophyte infection.
Dyshidrotic dermatitis
Sudden eruption of pruritic, small intradermal vesicles on hands and feet. There may be hx of contact irritants: for example, nickel.
Diagnosis is clinical. KOH microscopy is infrequently done, and rarely fungal culture or biopsy may be undertaken to exclude diagnosis of dermatophyte infection.
Lichen simplex chronicus
Leather-like, hyperpigmented patches that are pruritic and chronically rubbed, producing a leathery change in affected skin.
Diagnosis is clinical. KOH microscopy is infrequently done, and rarely fungal culture or biopsy may be undertaken to exclude diagnosis of dermatophyte infection.
Psoriasis
FHx of psoriasis, presence of characteristic silvery plaque and lesions located on extensor surface of elbows and knees will aid in diagnosis. View image Pitting of nails may be mistaken for tinea unguium. Clinical differentiation will usually suffice for tinea capitis, unguium, or corporis.
KOH microscopy is infrequently done, and rarely fungal culture or biopsy may be undertaken to exclude dermatophyte infection.
Trichotillomania
History of obsessive habit of twisting hair with fingers. Usually no inflammatory changes in scalp, and broken hairs are of different lengths.
Clinical diagnosis.
Traction alopecia
History of tightly braided hair styles. Broken hairs with patchy alopecia. Usually no scaling and inflammation of scalp.
Clinical diagnosis.
Alopecia areata
Complete rather than patchy hair loss.
Diagnosis is clinical. Skin bx will confirm diagnosis.
Erythema chronicum migrans
Rapidly enlarging and reddening, single or multiple bull's eye lesions on trunk. History of tick exposure or associated symptoms of Lyme disease.
Occasionally, KOH microscopy is required to distinguish this from tinea corporis. Antibody titres or skin bx for diagnosis of Lyme disease.
Pityriasis versicolor
Hypopigmented truncal lesions in dark-skinned individuals, darker than normal colour with scaling in light-skinned individuals; commonly, below neck level.
Clinical differentiation usually sufficient; occasionally KOH microscopy is required to distinguish this from tinea corporis.Ultraviolet light from Wood lamp shows a pale yellow-white fluorescence.
Pseudofolliculitis barbae
Hyperpigmented nodules in beard area with incurving hairs in patients with dark skin.
Clinical diagnosis.
Seborrhoeic dermatitis
Greasy and scaly area in scalp (with scaling but no hair loss, i.e., dandruff) and erythema in the nasolabial folds and occasionally central chest.
Clinical diagnosis.
Acne rosacea
Acneiform eruption with erythema and easy blushing in nasal and malar area.
Clinical diagnosis.
Discoid lupus erythematosus
Malar rash, sun sensitivity.
Skin bx is confirmatory.
Contact dermatitis
Pattern of eruption, intense pruritus, erythema, and occasional vesicular eruption.
Clinical diagnosis.
Candidal intertrigo
Usually uniformly red without central clearing or sparing of scrotum; satellite lesions.View image
Clinical differentiation usually sufficient from tinea cruris; responds to all topical therapies recommended for tinea cruris.
Erythrasma
Uniformly brown and scaly, with no active edge; groin or axillae.
Fluoresces a brilliant coral red under Wood lamp.
Friction blisters of feet
Absence of interdigital maceration or moccasin pattern of scaling; bulla primarily at points of contact with ill-fitting foot wear; acute in onset.
Clinical diagnosis.
Onychogryphosis
Long-standing thickening of toenails in which a hyperkeratotic, mis-shapen nail develops over months to years. Easily mistaken for tinea unguium, this change occurs in older adults where vascular disease and diabetes may play a role. Recurrent trauma (such as that caused by ill-fitting shoes) may play a role.
KOH microscopy of nail scrapings, fungal culture, or nail biopsy may be necessary to distinguish from tinea unguium; both conditions may co-exist.

Developmental dysplasia of the hip

Acetabular immaturity
Typically differentiated by the alpha-angle on ultrasound. However, interobserver reliability of this measurement may be suboptimal. [19] [20] [21]
Repeat ultrasound(s) over several weeks will typically differentiate from DDH before or by 3 months of age.
Proximal femoral focal deficiency
Thigh is large and markedly shortened.Sometimes associated with other skeletal anomalies such as fibular deficiency or knee hypoplasia.
Radiographically distinct; femur is always distinctly abnormal in appearance.
Residual effects of septic arthritis
Acute presentation with fever, irritability, poor feeding, pain on examination with internal rotation of flexed hip.
Radiographically distinct.X-ray may show avascular necrosis, varying degree of femoral head disruption/destruction.
Fracture of femoral neck
Uncommon in infancy.
Radiographically distinct.X-ray will show fracture.
Coxa vara
Uncommon disorder.Usually not appreciated until walking.70% of cases are unilateral with leg-length discrepancy noted.Physical examination: Trendelenburg gait.
X-ray will show decreased femoral neck-shaft angle on anterior-posterior view (demonstrating a varus deformity), vertical epiphysis.

Diabetes insipidus

Psychogenic polydipsia
Clinical signs and symptoms may be similar.
Following water deprivation test, urine osmolality will exceed serum osmolality.
Diabetes mellitus
Clinical signs and symptoms may be similar.Patients may have hx of existing diabetes mellitus (DM).However, it should be recognised that DM and DI (central or nephrogenic) can co-exist, and that DM may be a risk factor for central DI.
Fasting glucose and HbA1c are elevated.Following water deprivation test, urine osmolality will exceed serum osmolality.
Hyperaldosteronism
Symptoms of hypokalaemia are generally present. These include muscle weakness, paraesthesias, muscle cramps, nocturia, polyuria, and palpitations.Other non-specific symptoms include lethargy, difficulty concentrating, and mood disturbances such as irritability, anxiety, and depression.
Serum potassium is low.Plasma renin activity (PRA) may be abnormally low (<1 nanogram/mL/hour), and the plasma aldosterone concentration (PAC):plasma renin activity (PRA) ratio may be greatly elevated (>30 to 50; normal ratio is between 4 and 10).
Diuretics
Clinical signs and symptoms may be similar.Hx of diuretic use.
Serum potassium is low; urine potassium may be elevated.Following water deprivation test, urine osmolality will exceed serum osmolality.
Hyperosmolar hyperglycaemic state
Clinical signs and symptoms may be similar.
Plasma glucose >33.3 mmol/L (>600 mg/dL).Following water deprivation test, urine osmolality will exceed serum osmolality.

Diabetic cardiovascular disease

Unstable angina
Unstable angina presents as new onset of severe angina, angina at rest or minimal activity, or recent increase in frequency or intensity of chronic angina.
ECG typically shows ST depression and/or T-wave inversion for unstable angina. Troponin and CK-MB levels should be normal.
ST-elevation MI (STEMI)
Acute MI may present as new onset of severe angina, angina at rest or minimal activity, or recent increase in frequency or intensity of chronic angina.In a minority of people with diabetes, MI may present without symptoms.
ECG changes for STEMI include ST-segment elevation, T-wave inversion, and Q-wave formation. Troponin and CK-MB levels are elevated in acute coronary syndromes.
Non-ST-elevation MI (NSTEMI)
Acute MI may present as new onset of severe angina, angina at rest or minimal activity, or recent increase in frequency or intensity of chronic angina.In a minority of people with diabetes, MI may present without symptoms.
ECG typically shows ST depression and/or T-wave inversion for unstable angina and NSTEMI. Troponin and CK-MB levels are elevated in acute coronary syndromes.
Chronic stable angina
Patients typically present with exertional chest pain relieved by rest.
ECG is usually normal between episodes, but during angina episodes ST depression and/or T-wave inversion may be present. Cardiac enzymes are usually not elevated.
Congestive heart failure (CHF)
Symptoms of cough, SOB, orthopnoea, paroxysmal nocturnal dyspnoea, or peripheral oedema.Findings of jugular venous distention, pulmonary congestion, and S3 gallop.
Diagnosis can be made clinically, but several studies may assist if diagnosis is not clear.CXR may reveal cardiomegaly or pulmonary oedema.Serum brain natriuretic peptide is usually elevated.Echo provides information about left ventricular function, differentiates systolic from diastolic dysfunction, and identifies underlying valvular or structural heart disease.
Diastolic heart failure
Clinical syndrome of heart failure, with symptoms of pulmonary and peripheral congestion.
Normal left-ventricular systolic function and increased diastolic filling pressures on echo.
Transient ischaemic event (TIA)
Sudden onset of neurological deficit. Most TIAs last between 5 and 15 minutes.
Diagnosis is made by complete resolution of symptoms in <24 hours and no acute ischaemic findings on brain imaging. Acutely, non-contrast CT of the head is used to exclude intracerebral haemorrhage.
Ischaemic stroke
Sudden onset of neurological deficit. Symptoms lasting ≥24 hours are classified as a stroke.
CT or MRI will show ischaemic or haemorrhagic stroke. Acutely, non-contrast CT of the head is used to exclude intracerebral haemorrhage.
Haemorrhagic stroke
Sudden onset of neurological deficit. Symptoms lasting ≥24 hours are classified as a stroke.
Acutely, non-contrast CT of the head can show intracerebral haemorrhage.
Peripheral artery disease (PAD)
Pain, ache, cramp, or numbness in the muscles that develops with exercise and is relieved by rest. Pain in buttocks and thighs suggest aorto-iliac disease, while calf muscle pain suggests femoral or popliteal artery disease.
Ankle-brachial index (ABI) <0.9 indicates the presence of PAD in the legs.ABI <0.5 indicates severe PAD in the legs.In patients with symptoms of intermittent claudication, ABI should be repeated with exercise if the resting value is normal.

Diabetic ketoacidosis

Hyperosmolar hyperglycaemic state (HHS)
Patients are typically older than patients with diabetic ketoacidosis (DKA) and are usually patients with type 2 diabetes. Older nursing home residents with poor fluid intake are at high risk.Symptoms evolve insidiously over days to weeks.Mental obtundation and coma are more frequent. Focal neurologic signs (hemianopia and hemiparesis) and seizures are also seen. Seizures may be the dominant clinical features. [1] [18]
Serum glucose is >13.9 mmol/L (>600 mg/dL). Serum osmolarity is usually >320 mmol/ kg (>320 mOsm/kg).Urine ketones are normal or only mildly positive. Serum ketones are negative.Anion gap is variable but typically <12 mmol/L (<12 mEq/L).Total chloride deficit is 5 to 15 mmol/kg (5 to 15 mEq/kg).ABG: arterial pH is typically >7.30, whereas in DKA it ranges from 7.00 to 7.30. Arterial bicarbonate is >15 mmol/L (>15 mEq/L).
Lactic acidosis
The presentation is identical to that of DKA. In pure lactic acidosis, the serum glucose and ketones should be normal and the serum lactate concentration should be elevated.
Serum lactate >5 mmol/L. [1] [18]
Starvation ketosis
Starvation ketosis results from inadequate carbohydrate availability resulting in physiologically appropriate lipolysis and ketone production to provide fuel substrates for muscle.
The blood glucose is usually normal. Although the urine can have large amounts of ketones, the blood rarely does. Arterial pH is normal and the anion gap is at most mildly elevated. [1] [18]
Alcoholic ketoacidosis
Classically, these patients are long-standing alcoholics for whom ethanol has been the main caloric source for days to weeks. The ketoacidosis occurs when for some reason alcohol and caloric intake decreases.
In isolated alcoholic ketoacidosis, the metabolic acidosis is usually mild to moderate in severity. The anion gap is elevated. Serum and urine ketones are always present. Blood alcohol may be undetectable and patient may be hypoglycaemic. [1] [18]
Salicylate poisoning
Can be differentiated by history and laboratory investigation. Salicylate intoxication produces an anion gap metabolic acidosis usually with a respiratory alkalosis.
The plasma glucose is normal or low, ketones are negative, osmolality is normal and salicylates are positive in blood and/or urine. It should be noted that salicylates may cause false-positive or false-negative urinary glucose determination. [1] [18]
Ethylene glycol/methanol intoxication
Methanol and ethylene glycol also produce an anion gap metabolic acidosis without hyperglycaemia or ketones.
Methanol/ethylene glycol serum levels are elevated. They can produce an increase in the measured serum osmolality. [1] [18]
Uremic acidosis
It is characterised by markedly elevated serum urea and creatinine with normal plasma glucose. The pH and anion gap are usually mildly abnormal.
Elevated urea usually >71.4 mmol/L (200 mg/dL) and elevated creatinine usually >884 micromol/L (10 mg/dL). [1] [18]

Diabetic nephropathy

Non-diabetic kidney disease
Since both diabetes mellitus and chronic kidney disease (CKD) are common disorders, patients with both conditions may or may not have DN.A diagnosis other than DN should be considered if there is a rapid progression of renal failure, evidence of another systemic disease, or short duration of diabetes (although onset is insidious in type 2, and DN may occasionally be the presenting manifestation of type 2 diabetes mellitus).
Minimal proteinuria may indicate non-diabetic kidney disease.Other specific diagnostic tests for other systemic disorders associated with non-diabetic kidney disease may be positive (e.g., serum protein electrophoresis or serum free light chains in myeloma, ANA in SLE, ANCA in vasculitis, hypocomplementaemia in SLE, cryoglobulinaemia).
Multiple myeloma
Multiple myeloma (MM) patients also may present with renal failure and proteinuria.Symptoms of bone pain and anaemia are the most common presenting features, affecting 80% of patients with MM.
The characteristic test results that differ from DN are: the presence of paraproteinaemia/paraproteinuria; hypercalcaemia; impaired production of normal immunoglobulin; and lytic bone lesions. [17]Urinalysis with sulfosalicylic acid (SSA) was classically utilised to evaluate for discrepancy between albumin and total protein, as standard urinalysis dipstick detects albumin only. SSA causes precipitation of all of the urinary proteins, including paraproteins (Bence Jones proteins).Serum protein electrophoresis (PEP), urine protein electrophoresis (UPEP): paraprotein spike.Serum and urine free light chains: increased concentrations of free light chain in serum.Skull x-rays, CT, or MRI bone: lytic lesions.Bone marrow biopsy: plasma cell proliferation.
Renal tract obstruction
Can be caused by stones, cancer, fibrosis, prostate hypertrophy/cancer, neurogenic bladder, or pelviureteric junction obstruction.Obstruction to urine flow can result in post-renal failure. Symptoms include trouble passing urine, anuria, oliguria, haematuria, pain (with kidney stones), and urinary leakage/incontinence.Physical examination findings include enlarged prostate on rectal examination, costovertebral angle tenderness, suprapubic tenderness, and bladder fullness.
Passage of Foley catheter may result in flow of urine and relief of obstruction.Kidney ultrasound: hydronephrosis, stones.Prostate ultrasound: hypertrophy, cancer.CT abdomen: hydronephrosis, stones, mass, congenital abnormalities, fibrosis.PSA: elevated in BPH, prostate cancer.MRI: not routine but may show hydronephrosis, stones, mass, congenital abnormalities, fibrosis.
Glomerulonephritis
Glomerulonephritis, such as lupus nephritis and cryoglobulinaemia, is in the differential for DN.Patient presentation and physical examination may be similar to that of DN. However, there may be symptoms and signs of other systemic disease, such as rashes or joint involvement.
Urinalysis: haematuria, proteinuria, RBC casts, dysmorphic red cells.Albuminuria.Positive serology (e.g., ANA, ANCA, hepatitis serology).Complement: decreased in immune glomerulonephritis (e.g., lupus).Kidney biopsy: glomerulonephritis.
Renal artery stenosis
Renal artery stenosis presents either as HTN refractory to multiple maximised antihypertensives or as renal failure shortly after the initiation of an ACE inhibitor or angiotensin-receptor blockers (ARBs).Physical examination is significant for an abdominal bruit. [18]
Ultrasound, CT scan, MRI: shrunken kidney, decreased flow through the renal artery.Magnetic resonance angiography (MRA): renal artery stenosis.Renal angiogram: renal artery stenosis.

Diabetic neuropathy

Uraemia
Various signs associated with the primary cause for end-stage renal disease (ESRD) may be present.May co-exist with DN.
Abnormal urea, creatinine, GFR consistent with ESRD.
Cyanocobalamin deficiency
Poor nutrition, alcoholism, certain drugs (e.g., trimethoprim, methotrexate, phenytoin), pernicious anaemia, atrophic gastritis, malabsorption, or infection with Helicobacter pylori more likely to be present.Patients are more likely to be older (>65 years).
FBC reveals macrocytic anaemia.Reduced serum vitamin B12 levels.
Hypothyroidism
Fatigue, cold intolerance, weight gain, constipation, myalgia, menstrual irregularities, delayed relaxation of deep tendon reflexes, bradycardia (if severe).
TSH elevated in primary hypothyroidism.Free serum T4 may be low.
Acute intermittent porphyria
Abdominal pain, vomiting, muscle weakness, constipation, fever, diarrhoea, sensory loss, seizures, tachycardia, hypertension may all occur.Abdominal pain is severe and more typical than in DN.
Elevated aminolevulinic acid, porphobilinogen.
Chronic high alcohol intake
Signs of malnutrition, Wernicke encephalopathy, and Korsakoff amnestic syndrome may be present.
Severe cases present with associated anaemia, thiamine deficiency, and deranged LFTs.
Heavy metal poisoning
May present with a peripheral neuropathy that frequently manifests with extensor weakness, or wrist/ankle drop, due to an axonal degeneration, primarily affecting motor nerves.Abdominal pain ('lead colic'), constipation, joint pains, muscle aches, headache, anorexia, decreased libido, difficulty concentrating and deficits in short-term memory, anaemia, nephropathy, and other symptoms and signs in various combinations.
Abnormally high blood levels of lead or other metals.
Drug-induced neuropathy
Diabetes less likely and drug history likely to include a drug that is known to be a risk for development of neuropathy, such as (in descending order of likelihood of association) antivirals, antibacterials, antineoplastic and immunosuppressants, and cardiovascular, CNS, GI, and metabolism agents.History may include the following specific drugs suspected of causing neuropathies: stavudine, didanosine, lamivudine, thalidomide, ritonavir, zalcitabine, and amiodarone.
No differentiating investigations.
Chronic inflammatory demyelinating neuropathy (CIDP)
People with diabetes may develop features of CIDP.Severe, predominantly motor neuropathy that is progressive in nature. Features progress despite optimal glycaemic control.
May be difficult to differentiate.Nerve conduction studies show a combination of slowed conduction velocities, prolonged distal latencies, prolonged F-wave latencies, and conduction block in ≥1 nerves.Nerve biopsies demonstrate increased numbers of macrophages.Unusually high CSF protein.
Sarcoidosis
Various signs, including fever, skin signs (e.g., erythema nodosum), joint and/or eye lesions.
Chest x-ray may show bilateral hilar lymphadenopathy and pulmonary reticular opacities.Biopsies of accessible lesions are diagnostic.
Leprosy
Travel to or residence in endemic countries.Nerves commonly involved include the ulnar and median (claw hand), the common peroneal (foot drop), the posterior tibial (claw toes and plantar insensitivity), facial, radial cutaneous, and great auricular.
Skin smear is positive for acid fast bacilli (AFB).Biopsy of lesions reveal the presence of AFB plus other associated signs.
Polyarteritis nodosa (PAN)
Systemic symptoms (e.g., fatigue, weakness, fever, arthralgias) and signs (e.g., hypertension, renal insufficiency, neurological dysfunction, abdominal pain) of multisystem involvement more likely.
There is no diagnostic laboratory test for PAN.Basic laboratory tests help ascertain the extent of organs affected and their degree of involvement.
Amyloidosis
Muscle weakness and enlargement due to amyloid infiltration (myopathy), disorders of the joints (arthropathy), and lesions of bone (osteopathy) more likely to be present.
Presence of a paraprotein in the serum (as an M protein on protein immunoelectrophoresis or immunofixation) or urine (as monoclonal light chains) in approximately 90% cases.
Dysproteinaemias and paraproteinaemias
Possibly no differentiating signs or symptoms.
Presence of a monoclonal protein in the serum or urine.
Paraneoplastic syndrome
Varies, based on primary aetiology.History of a primary neoplastic condition.
Varies, based on primary aetiology.
Leukaemias and lymphomas
Symptoms and signs vary but may include anaemia, fever, weight loss, and lymphadenopathy.
Abnormal blood cell count and bone marrow aspirate.Specific abnormalities are diverse depending on the type of leukemia or lymphoma present.
Hereditary neuropathies (e.g., Charcot-Marie-Tooth disease)
Both motor and sensory nerve manifestations are more common with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.
Genetic testing is diagnostic.
Psychophysiological disorder
May also present with pains and paresthesias but without neurological deficit.There is no sensory loss.
Specific psychological evaluations help to confirm the diagnosis.
Multiple system atrophy/Shy-Drager syndrome
May present with symptoms and signs of autonomic neuropathy, as in DN.May also have parkinsonism, varying degrees of dysautonomia, cerebellar involvement, and pyramidal signs.
An excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis.
Riley-Day syndrome
Progressive sensorimotor neuropathy but sympathetic autonomic dysfunction is responsible for most clinical manifestations (i.e., orthostatic hypotension, swallowing dysfunction, GI motility dysfunction, bladder dysfunction, decreased or absent tearing, pupil dilation, hypohidrosis, and episodic hyperhidrosis).
Genetic evaluation is sensitive and specific for the diagnosis: a truncated form of I kappa B kinase complex associated protein (IKBKAP) mutation on chromosome 9q31.
Autonomic neuropathy: idiopathic orthostatic hypotension
Severe postural dizziness and weakness.
Reduction of systolic BP of at least 20 mmHg, or diastolic BP of at least 10 mmHg, within the first 3 minutes of standing.
Guillain-Barre syndrome
Progressive, fairly symmetrical muscle weakness accompanied by absent or depressed deep tendon reflexes.Weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles.
Albuminocytological dissociation in CSF (i.e., elevated protein with a normal WBC count), present in 80% to 90% patients at 1 week after onset of symptoms.
Myasthenia gravis
Fluctuating degree and variable combination of weakness in ocular, bulbar, limb, and respiratory muscles.
Antibodies against acetylcholine receptors or receptor associated proteins are present.Tensilon test, ice pack test, repetitive nerve stimulation studies, and single-fibre electromyography assist in confirmation of the diagnosis.
Degenerative spinal disk disease
May present with symptoms and signs of a femoral neuropathy, including asymmetrical pain weakness and sensory loss.
MRI demonstrates specific vertebral disk pathology.
Femoral neuropathy: intrinsic spinal cord mass lesion
May present with symptoms and signs of a femoral neuropathy, including asymmetrical pain, weakness, and sensory loss.
MRI demonstrates the spinal cord mass.
Cauda equina lesions
May present with symptoms and signs of a femoral neuropathy, including weakness and sensory loss.
Diagnosis usually confirmed by MRI.
Carotid aneurysm
May present with symptoms and signs of a cranial neuropathy, including diplopia and Bell palsy.
Magnetic resonance angiography and CT angiography confirm diagnosis.
Mononeuropathy multiplex: vasculitis
May present with symptoms and signs including nerve damage in ≥2 named nerves in separate parts of the body.Wrist drop, for example, is caused by infarction of the radial nerve, and foot drop by damage to either the sciatic or peroneal nerve.
Vasculitis and lymphocytic infiltrates on nerve biopsies.
Acromegaly
Very slow onset over decades.Typical clinical phenotype, including acral and soft tissue overgrowth; enlargement of jaw, nose, frontal bones, hands, and feet; articular overgrowth.
Abnormal IGF-1 levels.Pituitary MRI may reveal pituitary tumour.
Coagulopathies
May present with haemorrhages or thrombosis.
Abnormal platelets, prothrombin time, D-dimer, fibrinogen, fibrin degradation products.

Diabetic retinopathy

Ocular ischaemic syndrome
Commonly presents with amaurosis fugax and gradual or sudden visual loss. View imageVision may be poor, intraocular pressure may be abnormally high or low, and anterior segment neovascularisation is a common feature. [52]Commonly unilateral, predominantly haemorrhagic, and often involves equatorial and anterior retina rather than the posterior pole.
Fluorescein angiography shows delayed arterial filling in affected eyes.Doppler imaging may show carotid stenosis and ophthalmic artery flow reversal.
Radiation retinopathy
Typically occurs in people with a history of radiation exposure and without diabetes. View imageSigns of an irregular pattern of capillary leakage and non-perfusion are present.
No differentiating tests; exposure to radiation can usually be elicited from the history.
Retinal venous occlusion
Typically produces acute visual loss in one eye, and retinal signs (i.e., haemorrhage, cotton wool spots, macular oedema, neovascularisation) are limited to the eye and to the territory of the occlusion.Central retinal vein occlusion typically involves the posterior pole, View image but if a branch vein is occluded, signs are limited to the segment of retina drained by the vein, and it is usually possible to identify the point of occlusion where an artery crosses anterior to a vein. View image
Fluorescein angiography is effective in characterising the distinctly localised nature of vascular abnormality in retinal venous occlusion.
Hypertension
Systolic and diastolic pressures are markedly elevated.Associated with acute visual disturbance, with optic disc swelling (which is uncommon in diabetic retinopathy) and macular oedema often in the form of a macular exudate star.It may involve the posterior pole of both eyes, but signs of axoplasmic hold-up (i.e., cotton wool spots and optic disc oedema) tend to dominate the fundus appearance.
Fluorescein angiography reveals arteriolar non-perfusion, rather than capillary non-perfusion as in diabetic retinopathy.

Diastolic heart failure

Systolic heart failure
No differentiating signs or symptoms.
Echocardiogram allows for the measurement of the left ventricular ejection fraction (LVEF).
Obstructive lung disease
Dyspnoea and orthopnoea may be present, but usually not paroxysmal nocturnal dyspnoea. Usual precipitants are allergens, environmental triggers, and respiratory infection.
Pulmonary function testing will show an obstructive lung disease pattern, with or without improvement after using bronchodilators.
Idiopathic pulmonary arterial hypertension
Usually causes more prominent 'right-sided' heart failure symptoms, such as jugular venous distention and oedema. Rales usually absent.
Pulmonary pressures may be indirectly measured by Doppler echocardiography. On echocardiogram, left ventricular function is normal.The established standard for diagnosis of pulmonary hypertension is right heart catheterisation.
Pulmonary hypertension secondary to pulmonary disease
Dyspnoea is present due to lung pathology. Wheezing, rales, or rhonchi may be auscultated. 'Right-sided' heart failure symptoms such as jugular venous distention and oedema may also be present.
Pulmonary pressures may be indirectly measured by Doppler echocardiography. On echocardiogram, LV function is normal.The gold standard for diagnosis of pulmonary hypertension is right heart catheterisation.High-resolution CT scan may diagnose interstitial lung pathologies.CT angiography may diagnose pulmonary emboli up to the sub-segmental branch of the pulmonary arteries. Ventilation/perfusion scan may identify thromboembolic phenomena.Pulmonary function tests and sleep studies may diagnose obstructive and/or restrictive lung diseases that may lead to pulmonary hypertension.
Heart failure from high metabolic demand
Hx or physical manifestations of precipitating conditions (e.g., anaemia, arteriovenous fistulas, thyrotoxicosis, sepsis).
Investigations may include FBC, thyroid function tests, and blood cultures.
Non-cardiogenic pulmonary oedema
No differentiating signs or symptoms. Hx of high altitude, neurological event, post-transfusion or pulmonary embolism
Echocardiogram shows normal LV function. CXR shows normal heart size.

DiGeorge syndrome

Non-syndromic anomalies
The variable penetrance of DiGeorge may produce features that overlap with other syndromes.
Assessment for 22q deletions distinguishes most patients with DiGeorge syndrome from the non-syndromic variants of the specific anomalies.Routine screening of otherwise asymptomatic people with schizophrenia is generally not helpful.
Isotretinoin exposure
Fetal exposure to isotretinoins, such as those used for acne, causes the syndrome known as retinoic acid embryopathy, which can result in similar features to DiGeorge syndrome. [53] [54] [55] [56] A history of isotretinoin exposure is useful in differentiating this syndrome. More common in this syndrome than in 22qDS are microtia or anotia, micrognathia, and spontaneous abortion. [53]
Generally, these patients are missing the 22q deletion syndrome.
CHARGE syndrome
Infants with coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness (CHARGE syndrome) have features that may overlap with DiGeorge syndrome, and some patients described as having CHARGE syndrome have been found to have 22q deletions. [57] [58] [59] [60] [61] [62]
Some patients with CHARGE syndrome may have 22q deletions, while others will have CHD7 mutations. [60] Infants with CHARGE syndrome should have a T-cell count to exclude immunodeficiency.

Digoxin overdose

Beta-blocker toxicity
Hypotension, possible depressed mental status.
ECG (slow ventricular rate, AV nodal blockade with associated dysrhythmias).Blood glucose: hypoglycaemia.
Calcium-channel blocker toxicity
Hypotension, usually normal mental status.
ECG (slow ventricular rate, AV nodal blockade with associated dysrhythmias).Blood glucose: hyperglycaemia.
Clonidine toxicity
Hypotension, bradycardia, lethargy. Occasionally responsive to naloxone.
Normal or therapeutic serum digoxin concentration.
Hypothermia
Hypothermia, cool extremities, hypotension, ventricular dysrhythmias with rapid ventricular response.
Normal or therapeutic serum digoxin concentration.
Pesticide toxicity
Salivation, lacrimation, urination, and bronchorrhoea.
Normal or therapeutic serum digoxin concentration.
Ischemic heart disease
Hypotension, bradycardia, chest pain or discomfort, history of exertional dyspnoea with angina or anginal equivalent.
Normal or therapeutic serum digoxin concentration.
Acute MI
Chest discomfort and/or pain, dyspnoea, vomiting, pain characteristic of cardiac aetiology, bradycardia, hypotension.
Normal or therapeutic serum digoxin concentration.
Elevated intracranial pressure
Altered mental status, hypertension, sinus bradycardia (but could possibly have other bradycardic rhythms).
Normal or therapeutic serum digoxin concentration.
Hyperkalaemia
Patients with hyperkalaemia due to other aetiologies (e.g., diminished potassium excretion, excessive endogenous potassium load, pseudohyperkalaemia, redistribution from within cells into plasma) are typically awake and not lethargic.Patients with chronic renal insufficiency may present with lethargy and with any number of other non-specific complaints. Patients with hyperkalaemia may also present as completely asymptomatic.
Normal or therapeutic serum digoxin concentration.
Hypothyroidism
Cold intolerance, fatigue, depression, thinning of hair, lethargy, or abnormal menstrual cycle.
Elevated TSH and decreased T4 levels are useful in the diagnosis.

Diphtheria

Streptococcus pyogenes pharyngitis
Rapid onset with prominent sore throat and fever.Headache and gastrointestinal symptoms are frequent.Red throat and enlarged tonsils covered by yellow or blood-tinged exudate.Enlarged and tender cervical lymphadenopathy.Some patients have a fine papular rash with circum-oral pallor and strawberry tongue (scarlet fever). [23]
Positive throat culture is the definitive test for Streptococcus pyogenes diagnosis.Rapid antigen detection tests can confirm the presence of group A streptococci carbohydrate antigen on a throat swab within minutes. However, the sensitivity of these tests ranges between 70% and 90% compared with blood agar plate culture.
Acute epiglottitis
Acute fulminating course of high fever, sore throat, and rapidly progressing respiratory obstruction.Drooling is usually present, and patient maintains hyperextended neck in attempt to maintain open airways. [23]
Direct visualisation of the epiglottis shows cherry-red swollen area.A lateral x-ray of soft tissue of the neck shows enlarged epiglottitis protruding from the anterior wall of the hypopharynx (thumb sign).
Infectious mononucleosis
Prominent tonsillar enlargement with exudate and cervical lymphadenopathy.Hepatomegaly and splenomegaly usually present.Rash and generalised fatigue occur as part of infectious mononucleosis syndrome. [23]
Positive heterophil antibody test or positive serological test.
Acute necrotising ulcerative gingivitis (Vincent's angina)
Periodontal disease associated with spirochaetes and fusobacteria.Necrosis and ulceration of the gingiva between the teeth, with adherent greyish pseudomembrane covering the gingiva.Fever, malaise, and lymphadenopathy. [25]
Dark-field microscopy of debris from the pseudomembrane shows spirochaetes.
Staphylococcal or streptococcal impetigo
Typically affects the skin of the face or of extremities that have been traumatised.Tiny vesicles or pustules form initially and develop into small blisters that rupture, forming a honey-coloured, crusted plaque.Little or no pain. No surrounding erythema, and constitutional symptoms are generally absent. [21]
Bacteriological culture or microscopy shows staphylococci or streptococci.

Discoid lupus erythematosus

Systemic lupus erythematosus (SLE)
Skin manifestations are a common presentation of SLE. The photosensitive malar or butterfly rash is characteristic. This erythematous rash extends from the cheeks over the bridge of the nose, sparing the nasolabial folds. It can be painful and pruritic, usually lasts a few days, heals without scarring, but often recurs after sun exposure.For a diagnosis of SLE, ≥4 of the following 11 criteria are required: [12] 1) malar rash, 2) discoid rash, 3) photosensitivity, 4) oral ulcers, 5) arthritis, 6) serositis, 7) renal disorder, 8) neurological disorder, 9) haematological disorder, 10) immunological disorder, 11) ANA.
High-titre ANA, anti-double-stranded DNA antibodies, and anti-ribonucleoprotein antibodies are strongly suggestive.
Subacute cutaneous lupus erythematosus (SCLE)
SCLE lesions begin as small, erythematous, slightly scaly papules that evolve into either psoriasiform (papulosquamous) or annular forms. The lesions typically have erythematous crusted margins, usually sparing the face and mostly affecting the neck, arms, and upper torso.Although telangiectasia may be seen, permanent pigment changes and scarring are absent.
Findings on skin biopsy are similar to those of DLE, except that basement membrane thickening is generally absent or minimal.
Psoriasis
Lesions are red, inflamed, silvery-white scaly and circumscribed papules and plaques on elbows, knees, extensor limbs, and scalp. Psoriatic nails have a pitted surface and/or hypertrophic (subungual) changes.
Skin biopsy findings include intra-epidermal spongiform pustules and Munro neutrophilic microabscess within the stratum corneum.
Polymorphous light eruption (PMLE)
Considered an exclusively photo-triggered dermatosis that can express several clinical forms. PMLE lesions are usually itchy papules, eczematous plaques, or vesicles, often with associated urticaria, and develop within 24 hours of sun exposure.
Skin biopsy shows oedema in the upper part of the dermis.
Rosacea
Common chronic disorder of the skin characterised by redness, flushing, and other cutaneous findings that often include telangiectasias, roughened skin, rhinophyma, and general inflammation that can resemble acne.Typically affects the convexities of the central face, including the nose, cheeks, eyelids, and forehead. Papules and/or pustules occur in crops.
Skin biopsy shows non-specific granulomatous or lymphohistiocytic infiltrate. Associated oedema, telangiectasias, and sebaceous hyperplasia may also be present.
Lichen planopilaris
Refers to lichen planus of the hair follicles. Presents with alopecia associated with hyperkeratotic papules and perifollicular erythema.Typical lichen planus lesions affecting skin, nails, and buccal mucosa may also be present.
Skin biopsy shows lichenoid lymphocyte infiltrates under epidermis.

Disorders of infant feeding

Physiological gastro-oesophageal reflux (GOR)
Recurrent vomiting in the absence of other symptoms, with normal examination and growth.Regurgitation is more common after meals, and when the infant is in a recumbent position.
No diagnostic tests are required.Caregiver education and reassurance should be offered.
Malrotation with intermittent volvulus
Bilious vomiting.
Upper GI contrast study may be used to demonstrate abnormal anatomy.Abdominal ultrasound can demonstrate abnormal orientation of superior mesenteric vessels.
Intermittent intussusception
Vomiting and abdominal pain may be associated with pallor and passage of 'redcurrant jelly' stools.Abdominal mass may be palpable.
Abdominal ultrasound demonstrates telescoping of the bowel wall.Air enema demonstrates telescoping of bowel and may be therapeutic.
Hirschsprung's disease
Vomiting may be preceded by abdominal distension and constipation.A history of constipation back to neonatal period is usually reported, and there may have been delayed passage of meconium.
Rectal biopsy demonstrates absence of ganglionic cells.
Gastroenteritis
Acute change in bowel habit, and/or onset of vomiting.May have had exposure to people with similar symptoms, recent foreign travel, or recent dietary change.
Faecal sample for virology studies, microscopy, and culture help to identify causative organism.Faecal-reducing substances are positive in lactose intolerance secondary to infective gastroenteritis.
Eosinophilic oesophagitis
Symptoms of severe GORD associated with atopy.Failure to respond to acid-suppression therapy. [10]Difficult to distinguish from GORD, and is consequently found in 10% children undergoing endoscopy for investigation of severe reflux. [10]
Upper GI endoscopy with biopsy shows inflammatory changes of oesophageal mucosa, with predominantly eosinophilic infiltrate.
Hydrocephalus
Vomiting associated with altered alertness, change in head circumference, bulging fontanel, splayed sutures, and 'sun setting' of the eyes.
Cranial ultrasound as initial test for rapid assessment, followed by CT or MRI to guide neurosurgical management.
Subdural haematoma
Vomiting associated with altered level of alertness.Other signs of non-accidental injury such as bruising should be sought.
CT head shows subdural fluid collection.Further investigations for non-accidental injury should be considered, including skeletal survey and multidisciplinary review.
Intracranial mass lesion
Vomiting associated with altered level of alertness, seizures, or abnormal neurological examination.Signs of hydrocephalus may be evident.
CT head shows lesion.
Infection
Vomiting and altered feeding are more acute in nature.Associated with fever, tachypnoea, tachycardia, altered level of consciousness (increased irritability or lethargy), bulging fontanel, rash, high-pitched cry.Signs of otitis media include tense, bulging tympanic membrane, but this can be difficult to visualise in small infants.
Differentiating tests depend on severity and type of symptoms, and age at presentation.Diagnostic tests include FBC with differential, blood cultures, blood sugar, blood lactate, inflammatory markers such as procalcitonin and C-reactive protein, baseline renal and liver function, urinalysis plus culture, lumbar puncture with CSF virology, microscopy, and culture where indicated.
Metabolic conditions
Considered when symptoms begin after mild illness and period of decreased oral intake.Prolonged jaundice in neonate should be investigated for galactosaemia.
Tests include serum amino acid profile, lactate and ammonia, urinary organic acid profile.Gal-1-PUT (galactose-1-phosphate uridyltransferase) assay in galactosaemia.
Renal failure
May have history of abnormal renal scans prenatally, or family history of renal disease.May appear anaemic and yellow-tinged.Renal masses may be palpable.Hypertension may be present.
Renal function tests, blood gas to check pH and bicarbonate levels.Urinalysis shows haematuria and/or proteinuria.Renal ultrasound scan shows small kidney size, presence of obstruction/hydronephrosis, or kidney stones.
Poisoning
Usually more acute presentation.Vomiting may be associated with altered consciousness level, seizures, or altered neurological examination.Social history, to include living environment, exposure to hazardous materials, and contact with medications in the home, may reveal source of poison.
Dictated by history and possible poison.May include blood tests to check for pancytopenia, altered liver and renal function, toxin levels.ECG may be indicated to identify arrhythmias.Further investigation/management as advised by Poisons Unit.

Disseminated intravascular coagulation

Severe liver failure
Most common differential diagnosis and a known underlying cause of DIC. [1] [2] [4]Absence of symptoms and signs related to thrombosis in the patients without DIC.
LFTs: elevated; varies depending on aetiology.INR >1.5.Fibrin degradation products (FDPs), D-dimer test, and platelet count may help to differentiate this from DIC.FDPs: normal level; D-dimer test: negative.
Heparin-induced thrombocytopenia
Hx of use of heparin in association with low platelet count, plus absence of triggering factors for DIC
Heparin aggregation study: presence of platelet aggregation when exposed to heparin (caused by antibodies to platelet factor 4).FBC: low platelet count; FDPs: normal level; D-dimer test: negative.
Idiopathic purpura fulminans
Purpuric skin lesions that characteristically have well-demarcated borders.Usually associated with sepsis and is a known underlying cause of DIC.The idiopathic variety is often confined to the skin.
FDPs and D-dimer test may help to exclude DIC, but many patients will develop DIC.FDPs: normal level; D-dimer test: negative.
Vitamin K deficiency
Positive symptoms and signs of bleeding, but negative symptoms and signs of thrombosis.Associated with a poor diet (e.g., bulimic anorexia, alcoholism) and conditions that affect GI absorption (e.g., cystic fibrosis, inflammatory bowel disease, primary biliary cirrhosis).
Vitamin K level: decreased.INR: elevated.FDPs: normal level; D-dimer test: negative.
HELLP syndrome
Usually occurs after 28 weeks' gestation in pregnant women; can also occur postpartum.Key clinical picture: severe pregnancy-induced hypertension, elevated liver enzymes, and low platelets.Also a known underlying cause of DIC, but negative symptoms and signs of thrombosis.
FBC: low platelets, anaemia may be present.LFTs: elevated ALT and AST.FDPs: normal level; D-dimer test: negative (unless has progressed to DIC).Coombs' test: positive.

Diverticular disease

Colorectal cancer
History of altered bowel habits, anaemia, colonic polyps, and positive FHx are suggestive of colorectal cancer.
CT scan features of carcinoma include mass, stricture, and obstruction.Anaemia is frequent in colon cancer, whereas polymorphonuclear leukocytosis is a feature of acute diverticulitis.
Appendicitis
Patients with acute appendicitis are usually younger than those with acute diverticulitis.Pain localises to right lower quadrant in appendicitis and to left lower quadrant in diverticulitis, with exception of less common right-sided diverticulitis.
CT scan may reveal characteristic changes of acute appendicitis. This may be enlarged diameter of appendix more than 6 mm with associated periappendiceal inflammation.
Ulcerative colitis
Usually presents at a younger age, but incidence increases again at about 70 years of age. [24]Family history and white ethnicity common. [24] [25]
Limited flexible sigmoidoscopy in early stages reveals diffuse inflammation and ulceration in cases of acute ulcerative colitis. [26] Colonoscopy and biopsy performed subsequently. Antineutrophil cytoplasmic antibodies in antibody test are present in >65% cases of ulcerative colitis.
Crohn's disease
Usually presents at a younger age, but incidence increases again at about 70 years of age. [24]Family history and white ethnicity common. [25] [24]
Anti-Saccharomyces cerevisiae in antibody blood test may indicate Crohn's disease; present in >65% of patients. Colonoscopy and biopsy performed subsequently.
Urinary tract infection
Frequency, urgency, burning, dysuria, lower abdominal pain.
Urinalysis with UTI will show increased leukocyte count, bacteria, and presence of nitrites.
Pyelonephritis
Fever, chills, leukocytosis, flank pain, and renal tenderness.
Urinalysis with pyelonephritis will show increased leukocyte count, bacteria, and presence of nitrites.
Ischaemic colitis
Usually occurs in older people with evidence of generalised atherosclerosis, and presents with abdominal pain and rectal bleeding.
Abdominal radiographs may show oedema of bowel wall and minute ulcers thumb printing in the right colon with ischaemic colitis.CT scan with ischaemic colitis shows similar changes in a more precise fashion and angiography confirms the diagnosis.Limited flexible sigmoidoscopy without air insufflation may be helpful in identifying ischaemic mucosa.
Pelvic inflammatory disease
Urethral/vaginal discharge evidence of STD; cervical motion tenderness.
Isolation of organisms in urethral/vaginal swabs by direct microscopy, culture, or other available tests.
Irritable bowel syndrome
Usually occurs in younger patients with presence of Rome III criteria and absence of evidence of systemic illness. [27]
Normal laboratory tests and imaging studies.

Down's syndrome

Isolated hypotonia
Hypotonia during infancy but no associated dysmorphic features or congenital defects.
Normal karyotype.
Zellweger's syndrome
Peroxisomal disorder with hypotonia, flat occiput and face, epicanthal folds, Brushfield spots, cataracts, single palmar crease, seizures.Difficult to distinguish clinically.
Elevated very long chain fatty acids in plasma.Normal karyotype.

Dry eye

Red eye
Signs and symptoms may be very similar to dry eye.
There are no specific tests to differentiate between dry eye and red eye. Dry eye should always be considered in the differential diagnosis of red eye.
Primary Sjogren's syndrome
Symptomatic dry mouth and fatigue as well as dry eyes.Oral symptoms can be determined with positive responses to at least one of the following questions: Have you had a daily feeling of dry mouth for more than 3 months? Have you had recurrently or persistently swollen salivary glands as an adult? Do you frequently drink liquids to aid in swallowing dry food? [1]
Salivary function tests show sialectasia (salivary duct dilatation) and delayed or absent secretion of labelled saliva. [1]FBC results show anaemia in 25% of patients. [1]Serology reveals antibodies to Ro (Sjogren's syndrome antigen A [SSA]) or La (Sjogren's syndrome antigen B [SSB]) antigens, or both are present in serum. [1]
Secondary Sjogren's syndrome
Patients with symptomatic dry mouth and fatigue as well as dry eye may have histories and examination findings that point to other underlying connective tissue disorders. For example, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and/or mixed connective tissue disorder.Oral symptoms can be determined with positive responses to at least one of the following questions: Have you had a daily feeling of dry mouth for more than 3 months? Have you had recurrently or persistently swollen salivary glands as an adult? Do you frequently drink liquids to aid in swallowing dry food? [1]
Salivary function tests show sialectasia (salivary duct dilatation) and delayed or absent secretion of labelled saliva. [1]FBC results show anaemia in 75% of patients. [1]Serology reveals antibodies to Ro (SSA) or La (SSB) antigens, or both are present in serum. [1]
Meibomian gland dysfunction
Past ocular and/or medical history may indicate meibomian gland dysfunction.Scalp changes including seborrhoeic dermatitis and/or flaking/greasy skin may be present.
Slit-lamp tests reveal unstable tear film with rapid tear break-up time.

Dubin-Johnson syndrome

Rotor's syndrome
Clinically indistinguishable.
Urinary coproporphyrin: 2.5 to 5 times higher than normal, but isomer I <80% of total.Liver biopsy: pigmentation not seen.Oral cholecystograms shows normal gallbladder opacification.
Gilbert's syndrome
Presents with jaundice. Very rare before puberty.
Unconjugated hyperbilirubinaemia but usually <52 micromol/L (<3 mg/dL) and invariably <102 micromol/L (<6 mg/dL).Liver biopsy: usually normal; may have accumulation of a lipofuscin-like pigment around the terminal hepatic venules.
Crigler-Najjar syndrome (type I and II)
Type I usually diagnosed during the neonatal period, and jaundice is more severe. Type II may present during infancy.
Unconjugated hyperbilirubinaemiaBilirubin level of 290 to 855 micromol/L (17 to 50 mg/dL) in type I and102 to 376 micromol/L (6 to 22 mg/dL) in type II.
Cholecystitis
Right upper quadrant (RUQ) tenderness, positive Murphy sign, may have RUQ mass. Previous episodes of similar pain often noted.
LFTs: elevated alkaline phosphatase, gamma-glutamyl transferase, and bilirubin.Ultrasound of the gallbladder: pericholecystic fluid, distended gallbladder, thickened gallbladder wall, gallstones.
Extrahepatic biliary obstruction
Pruritus and pale stools.
Elevated alkaline phosphatase.Elevated gamma-galactosyl transferase.CT of the biliary tree will demonstrate level and nature of obstruction.
Familial intrahepatic cholestasis
Pruritus, hepatosplenomegaly, diagnosis usually at <1 year of age, dark urine, pale stools.
Elevated bile acids.Elevation of serum alkaline phosphatase.Elevation of faecal fat.Liver biopsy: characteristic appearance of hepatocellular cholestasis with giant cells with or without fibrosis.
Benign recurrent intrahepatic cholestasis
Recurrent attacks of cholestasis lasting days to months. Each episode preceded by intense pruritus, malaise, and sometimes diarrhoea. Pale stools often seen. Between episodes, patients are asymptomatic.
During an episode, LFTs will reflect cholestasis with elevated serum bile acids and alkaline phosphataseBiopsy specimens during an attack show bile plugs within the ducts.Between attacks, liver histology is normal apart from mild portal zone fibrosis. [32] [33]

Dupuytren's contracture

Trigger finger
The finger can be fully extended with a notable click.
Ultrasound: thickening and hypoechogenicity, with possible increased vascularity of the A1 pulley.
Epithelioid sarcoma
Tends to be progressive and extend beyond localised digits.
Biopsy: results can be difficult to determine but are often seen as well-defined eosinophilic cytoplasms and one or more atypical, eccentrically located nuclei, resulting in a plasmacytoid appearance.
Camptodactyly
Presence of little finger contracture from an early age.
No differentiating tests.
Traumatic finger contracture
History of significant preceding trauma leading to injury of the proximal interphalangeal joint.
X-ray of hand may show associated fracture.

Dysbarism

Gas toxicity (decompression illness)
Contamination of breathing gas is rare, but carbon monoxide poisoning has occurred, causing symptoms such as headache, delirium, and loss of consciousness. [39] The gas may smell or taste oily, and symptoms may be present in other divers who have breathed gas from the same source.
Analysis of the breathing gas and measurement of carboxy-haemoglobin levels will confirm exposure.
Hypercapnia
Strenuous exertion or 'skip breathing' (intentional hypoventilation) while underwater can cause severe headache during or after a dive. Decompression illness will normally exhibit other features in addition to headache.
Diagnosis is clinical.
Hyperventilation
May cause transient peripheral paraesthesia in the hands, especially if the diver is anxious or dyspnoeic. Accompanying subjective dizziness or perceptual disturbances may complicate diagnosis, but the symptoms subside once the diver is calm, or are relieved by re-breathing into an airtight container.
Diagnosis is clinical.
Near drowning
An obvious history of water aspiration favours near drowning, whereas in decompression illness symptoms in other systems are often present. However, cardiopulmonary manifestations of decompression illness may resemble those of near drowning (dyspnoea, cough, chest pain, pulmonary oedema). The two diagnoses may co-exist, and if in doubt, recompression is advised.
CXR may show signs of water aspiration.
Pulmonary oedema
Immersion in water may spontaneously cause pulmonary oedema, and exertion at depth may precipitate cardiac failure. [40]Symptoms are pulmonary only (rather than multi-system, as in decompression illness) and develop at depth (rather than during or after ascent, as in decompression illness). The symptoms become worse during ascent, since available oxygen diminishes. Difficult to distinguish clinically from pulmonary barotrauma in the acute setting.
CXR may show signs of acute pulmonary oedema.
Congestive heart failure
Immersion in water may spontaneously cause pulmonary oedema, and exertion at depth may precipitate cardiac failure. [40]Symptoms are pulmonary only (rather than multi-system, as in decompression illness) and develop at depth (rather than during or after ascent, as in decompression illness). The symptoms become worse during ascent, since available oxygen diminishes. Difficult to distinguish clinically from pulmonary barotrauma in the acute setting.
CXR may show signs of acute pulmonary oedema.
Envenomation or toxin ingestion
Suggested by a history of fish or shellfish ingestion, or by a bite, sting, or unusual mark on examination. Marine animal envenomation or ingestion of seafood toxins can produce a wide range of local and systemic symptoms consistent with decompression illness.
Diagnosis is clinical.
Migraine
Diving can trigger an attack and symptoms such as headache, visual disturbance, and hemiparesis. Divers with a history of migraines whose symptoms conform to their stereotype can be observed initially, but atypical features or deterioration should prompt recompression.
Diagnosis is clinical.
Cerebrovascular event
May present similarly to arterial gas embolism (AGE) or cerebral decompression sickness. Symptom onset within a few minutes of diving is more likely to be due to AGE.
CT of the head demonstrates ischaemia or haemorrhage.
Minor head injury
May present similarly to cerebral decompression illness. There may be a history of head trauma or evidence on physical examination.
Diagnosis is primarily clinical. CT of the head may demonstrate injury.
Acute coronary syndrome
Acutely, there are no differentiating symptoms or signs, and chest pain and dyspnoea relieved by oxygen may be confused with cardiopulmonary decompression illness or pulmonary barotrauma.
ECG may show arrhythmias or typical ischaemic changes (e.g., ST elevation).Coronary angiography may show abnormal blood flow.Serum creatine kinase may be elevated, but it can also be elevated in divers with AGE. [41]
Seizure disorder
A seizure due to epilepsy, an undiagnosed space-occupying lesion, or hypoglycaemia in a diabetic diver may be difficult to differentiate clinically from decompression illness.
EEG may show epileptiform activity.MRI may demonstrate a space-occupying lesion.Blood glucose level may be low.
Multiple sclerosis
Acutely there are no symptoms or signs to differentiate between a first presentation or an exacerbation of multiple sclerosis and neurological manifestations of decompression illness.
MRI may show patches of demyelination.
Guillain-Barre syndrome
Acutely there are no symptoms or signs to differentiate between Guillain-Barre syndrome and neurological manifestations of decompression illness.
CSF protein may be elevated. EMG and nerve conduction studies may show conduction slowing.
Acute transverse myelitis
Acutely, there are no differentiating symptoms or signs between neurological manifestations of decompression illness and acute transverse myelitis. May cause diagnostic confusion with neurological decompression illness.
MRI of the spinal cord shows intrinsic lesions, confirming myelopathy. CSF may show pleocytosis, elevated protein, abnormal immunoglobulin production, and oligoclonal bands.
Spinal cord compression
Acutely, there are no differentiating symptoms or signs, and divers are prone to disc herniation through bending and straining and from lifting heavy or wet diving equipment.
MRI of the spinal cord reveals a disc lesion.
Sprains and strains, tenosynovitis
History and examination may point to a traumatic cause for musculoskeletal pains, which are common in divers. Migratory or diffuse symptoms that are not attributable to other causes, especially if associated with symptoms in other systems, should prompt consideration of recompression.
Diagnosis is clinical.
Infection
Non-specific malaise and generalised myalgia may be mistaken for the constitutional symptoms of decompression illness. Usually, clear features of infection will be present, such as fever, rhinorrhoea, or productive cough, with supportive signs on examination.
Diagnosis is clinical. WBC may be elevated.
Drugs
The effects of chronic analgesic or sedative medication over-use, and the adverse effects of certain drugs (e.g., mefloquine), may mimic subjective symptoms of decompression illness. [42] Temporal relation of symptoms to drug ingestion may be diagnostic.Acute intoxication or hangover may cause neurological or behavioural changes, headache, nausea, and visual disturbances consistent with nitrogen narcosis. A history of ingestion together with the persistence of symptoms after ascent is diagnostic.
Diagnosis is clinical. Blood or urine testing may be positive for illicit substances.
Psychological problems, acute psychosis
Inexperienced divers or those of a nervous disposition may focus on subjective symptoms to such an extent that exclusion of decompression illness may be impossible without recompression.Acute psychosis with thought disorder, delusions, or hallucinations may mimic nitrogen narcosis. Symptoms that persist after a return to atmospheric pressure are suggestive, whereas rapid reversibility of the symptoms with ascent generally confirms the diagnosis of nitrogen narcosis.
Diagnosis is clinical.
Pulmonary embolism
May present with chest pain and dyspnoea. Difficult to distinguish clinically from barotraumas in the field.
D-dimer may be positive. ECG changes may include tachycardia, right axis deviation, right bundle branch block, or the classic S wave in lead I and Q wave with T wave inversion in lead III.
Pneumonia
A history of fever or respiratory complaints before diving may be suggestive. Signs may include a cough productive of coloured sputum, and rigors.
CXR may demonstrate consolidation or effusion. WBC may be elevated, and sputum culture positive.
Acute exacerbation of asthma
A past medical history of asthma in a diver needs careful assessment. Dry compressed gas, exercise, saltwater aspiration, and anxiety are all potential triggers for an asthma attack while diving. Wheeze and diurnal variation of symptoms are rare in pulmonary barotrauma.
Inhalation of a beta-2 agonist will improve symptoms, and can be used to test the diagnosis.
GORD
Can occur during immersion, even with a normal lower oesophageal sphincter. [43] Symptoms of reflux and aspiration of gastric contents may be similar to those of pulmonary barotrauma, although a prior history of GORD may be present.
Diagnosis is clinical.
Costochondritis
Inflammation of the costochondral or costosternal joints may cause pleuritic chest pain. There is localised tenderness on palpation, and lung fields are clear on auscultation.
Diagnosis is clinical.
Rib fracture
A fractured rib may cause pleuritic-type chest pain. There may be a history of chest trauma. There is localised tenderness on palpation, and lung fields are clear on auscultation.
CXR will reveal a fracture.
Otitis externa
'Swimmer's ear' may cause itching, a purulent discharge, or an inflamed pinna. Pushing the tragus classically causes pain. Otoscopy may show a swollen, eczematous external ear canal.
Diagnosis is clinical.
Otitis media
Common on dive trips, and symptoms may mimic those of middle-ear barotrauma. Otoscopy may show a purulent discharge.
Diagnosis is clinical.
Mastoiditis
Untreated otitis media may occasionally progress to mastoiditis, with swelling and tenderness over the mastoid process.
Diagnosis is clinical.
Alternobaric vertigo
Asymmetric middle-ear pressures on ascent may lead to unequal vestibular end-organ stimulation. This can be distinguished from ear barotrauma by its transient nature and the absence of otoscopic abnormalities.
Diagnosis is clinical.
Labyrinthitis
A history of recent upper respiratory tract infection may suggest labyrinthitis. Otherwise difficult to differentiate from ear barotrauma.
Diagnosis is clinical.
Meniere's disease
May present in a similar fashion to ear barotrauma. The attacks of vertigo tend to be unpredictable, severe, and incapacitating. Many patients have a family history. May be associated with hearing loss and tinnitus.
Diagnosis is clinical.
Sinusitis
A thick, purulent nasal discharge and fever may help to distinguish sinus infection from sinus barotrauma.
Elevated WBC.
Dental infection
Pain felt in the teeth may be due to local infection, referred pain from ipsilateral maxillary sinus barotrauma, or barodontalgia (caused by pressure changes in or around the teeth themselves). Clinically difficult to differentiate, although a single affected tooth is more likely to represent infection.
Elevated WBC in infection.
Epistaxis
Vigorous equalising manoeuvres may cause epistaxis through localised shearing of nasal blood vessels, with the appearance of blood in the diving mask. In contrast to sinus barotrauma, pain is usually absent.
Diagnosis is clinical.
Hypoglycaemia
May be difficult to differentiate clinically from nitrogen narcosis, particularly in diabetic divers, and is one reason why this group is limited to depths not exceeding 30 m (98 feet). [44]
Low blood glucose level.

Dysfunctional uterine bleeding

Pregnancy-related bleeding
A positive pregnancy test should alert attention toward problems associated with pregnancy; most commonly miscarriage and most seriously ectopic pregnancy.
Positive pregnancy test (urine or blood pregnancy test). Sensitive urine pregnancy tests can detect pregnancies as early as a few days following a missed period.Beta-hCG levels <5 IU/L (<5 mIU/mL) exclude pregnancy.
Iatrogenic uterine bleeding
History of medicines use including contraceptives, OTC medicines, and herbs are important clues in the aetiology of abnormal uterine bleeding. [1] [11]Anticoagulants are relatively common causes of abnormal uterine bleeding.Administration of sex hormones (e.g., oestrogen and progesterone) or other substances with sex hormone activity (e.g., phyto-oestrogen in some herbs and certain foods) can be associated with abnormal uterine bleeding. [11]
No differentiating tests: diagnosis is clinical.
Endocrine disorders
Symptoms of hyper- or hypothyroidism or hyperprolactinaemia may be present.The mechanism is due to interference with normal ovulation and normal sequential production of oestrogen followed by oestrogen and progesterone after ovulation. [11]
For thyroid disorders, TSH will usually be abnormal.Raised serum prolactin levels may be present in cases of hyperprolactinaemia.
Blood diseases
Easy bruising, excess bleeding at sites of trauma.Blood diseases associated with tendency for excessive bleeding can be associated with menorrhagia. This includes bleeding disorders (e.g., haemophilia) and blood dyscrasias (e.g., leukaemia and thrombocytopenia). [1]
Screening blood tests including FBC and coagulation profile.
Genital tract neoplasms
Symptoms may include mass effect from large neoplasms.Benign neoplasms including uterine leiomyoma are one of the most common causes of abnormal uterine bleeding.Malignant genital tract neoplasms can present with abnormal uterine bleeding. This is particularly true with uterine and cervical cancer. Pre-malignant situations, such as endometrial hyperplasia, are also possible causes. [1]
Imaging, such as pelvic and vaginal ultrasound, CT scan, and MRI will show lesion.Definitive diagnosis usually requires tissue biopsy (e.g., endometrial sampling, hysteroscopic sampling, D&C). However, leiomyomas are usually diagnosed by clinical examination and ultrasonography. [1]
Genital tract infections
Genital infections including cervicitis, endometritis, and rarely, salpingitis, can be associated with abnormal bleeding. [11]The history and physical examination, notable for sexual contact, vaginal discharge, cervical excitation, and/or suprapubic tenderness, are usually enough to suspect diagnosis.
Positive cervical swab culture.
Genital trauma
It may be difficult to differentiate between uterine bleeding and bleeding coming from other parts of the genital tract.Injury during intercourse and physical abuse are important aetiologies that should always be kept in mind.Careful history and physical examination is usually sufficient for diagnosis.
Examination under anaesthesia may be required to diagnose the extent of genital injury.

Dyshidrotic dermatitis

Tinea manus/pedis
Tinea may rarely present with vesicles.Patients with tinea often have prominent scale and may also have maceration, especially between the fourth and fifth toes, and thickened toenails (onychomycosis).
Potassium hydroxide (KOH) prep will be positive, with fungal hyphae appreciated, in tinea.Consider sending a skin scraping for fungal culture if further confirmation is desired.
Palmoplantar psoriasis
Pustular palmoplantar psoriasis is characterised by pustules of the palms and soles, as opposed to the vesicles of dyshidrotic dermatitis.Classic lesions of psoriasis (thick, scaling plaques on the elbows and knees) are often present.
Skin biopsy of dyshidrotic dermatitis will reveal spongiotic dermatitis.Psoriasis will have characteristic findings such as psoriasiform hyperplasia and Munro micro-abscesses.
Allergic contact dermatitis
History may reveal exacerbating factors in contact allergy. In addition, the lesions are more inflammatory than those of dyshidrotic dermatitis.Allergy to topical corticosteroids can be a particularly vexing problem because the dual competing effects of applying the medication in this situation are decreasing inflammation and propagating the allergic response.
Patch testing confirms suspected contact allergy.
Scabies
Erythematous papules, especially in the finger webs on the hand.Excoriated papules are likely to be found elsewhere in scabies infestation, especially the genital region and umbilicus.Burrows may be seen.Close contacts of the patient will often have a similar eruption.
A therapeutic trial with a parasiticidal preparation will distinguish scabies from dyshidrotic dermatitis.
Pemphigus
Pemphigus involves skin other than acral sites.
Skin biopsy will have positive immunofluorescence and characteristic findings on histopathology.
Bullous pemphigoid
Bullous pemphigoid involves skin other than acral sites.
Skin biopsy will have positive immunofluorescence and characteristic findings on histopathology.

Dyssomnias in children

Primary snoring
Snoring, often intermittent and in association with nasal congestion, without diminished airflow through the upper airway. Still unclear at what point primary snoring begins to impact behaviour and cognition. [63]
Polysomnography (PSG) shows airflow through the upper airway unchanged or not diminished by <50% of baseline; no association of snoring with desaturations or arousals.
Central sleep apnoea
Pauses in breathing lasting >20 seconds, or associated with arousal or desaturation without accompanied respiratory effort.
PSG shows discrete events of decrease in airflow 90% or more, lasting >20 seconds or associated with desaturation 3% or more, and/or arousal, which are not accompanied by respiratory effort.
Anxiety
Refusal to sleep alone or in own bedroom because of underlying anxiety; can be confused with limit-setting disorder.
No differentiating tests.
Post-traumatic stress disorder (PTSD)
Refusal to sleep alone or in bedroom because of PTSD; can be confused with limit-setting disorder.
No differentiating tests.
Restless legs syndrome
Vague sensations of discomfort that get worse in the evening and at rest, and are alleviated with movement.
Diagnosis is history-based. PSG can show periodic limb movements, which are often found in association with the syndrome. [59] [64]
Depression
Depressed affect, early morning awakenings.
No differentiating test.
Periodic limb movement disorder
Repetitive, stereotypical limb movements often associated with arousal, not explained by other underlying medical issue.
PSG showing runs of at least 4 repetitive limb movements lasting 0.5 to 10 seconds occurring every 5 to 90 seconds.
Frontal lobe epilepsy
Unusual movement and or vocalisation arising from sleep; often mistaken for confusional arousals or parasomnias.
PSG with video recording; full or extended EEG montage. Abnormal EEG activity (spike/sharp/spike and wave discharge) associated with the activity in question.
Non-REM parasomnias
Sleepwalking, sleep talking, and unusual activity of which the subject has no recollection of in the morning. Often elicited by insufficient sleep, irregular schedule, inconsistent sleep environment, or fever.
No differentiating test.
REM behaviour disorder
Violent acting out of dreams; associated with narcolepsy and, in adults, with neurodegenerative disease.
PSG demonstrates correlation of violent behaviour with REM sleep.
Night terrors
Episodes of screaming, yelling, incoherent moaning, diaphoresis, and visible anxiety lasting 10 to 20 minutes during which the child is inconsolable. There is no recollection of the event in the morning. Usually occur in the first half of the night.
No differentiating test.
Nightmares
Vivid, frightening dreams that the child awakens from and has good recall of.
No differentiating test.
Insufficient sleep
Inadequate amount of time devoted to sleep.
No differentiating test.
Jet lag-type circadian rhythm disorder
Discoordinated sleepiness and wakefulness with external clock following travel across time zones; reflects dyssynchrony of external and circadian clocks.
No differentiating test.
Advanced sleep phase disorder
Tendency to become very sleepy in the early evening, and to arise early in the morning. Uncommon in children.
No differentiating test.
Medication-induced abnormality
Difficulty initiating, maintaining sleep; excessive daytime sleepiness, vivid dreams and nightmares, increased limb movements, symptoms of restless legs syndrome. Discontinuation of inciting drug may improve symptoms.
No differentiating test.
Too much time in bed
Difficulty initiating, maintaining sleep; child spending more time in bed than age-appropriate sleep requirements.
No differentiating test.
Hypnic jerks
Involuntary jerks of one or more muscle segments during wake-sleep transition.
No differentiating test.
Autism
Underlying autistic disorder with difficulties initiating and/or maintaining sleep.
No differentiating test.
Primary nocturnal enuresis
Primary nocturnal enuresis refers to intermittent bed wetting in a child who has never been dry. The child must be at least 5 years old to make the diagnosis.Secondary nocturnal enuresis refers to intermittent bed wetting in a child who has previously been dry for at least 6 months.
No differentiating test.
Colic
Crying in evening in infants lasting 3 or more hours/day, for 3 or more days/week, for 3 or more weeks. [65]
No differentiating test.
Food allergies
Nocturnal awakenings secondary to discomfort.
Elimination trial of specific food.
Ear infection
Nocturnal awakenings secondary to ear discomfort.Physical examination with finding of inflamed tympanic membrane.
No tests usually needed.
Asthma
Nocturnal awakenings secondary to breathing discomfort. Physical examination with findings of wheeze, prolonged expiratory phase.
Spirometry showing reversible obstructive defect.
Post-traumatic hypersomnolence
Excessive daytime sleepiness following head trauma.
No differentiating test.
Smith-Magenis syndrome
Disrupted sleep patterns, in setting of developmental delay; dysmorphic features. In the differential for difficulty initiating and maintaining sleep. Rare.
Chromosome 17p microdeletion present, increased melatonin secretion during the day. Response to melatonin at night and beta-blockers during daytime.
Kleine-Levin syndrome
Episodic hypersomnolence, hyperphagia, hypersexuality. In the differential for hypersomnolence. Rare.
No differentiating test.

Dysthymia

Major depressive disorder
A major depressive episode is defined as having 5 of 9 symptoms (by DSM-IV-TR) present nearly every day for 2 weeks or longer.In chronic major depressive disorder, the symptoms of a major depressive episode are present nearly every day for 2 years or more.
Clinical diagnosis.Meets DSM-IV-TR diagnostic criteria for major depressive disorder.
Major depressive disorder in incomplete remission
Major depressive episode at start of dysthymia.
Clinical diagnosis using DSM-IV-TR criteria.This diagnosis is given if the dysthymia begins with a major depressive episode.
Bipolar disorders (bipolar I, bipolar II, bipolar disorder not otherwise specified)
Manic, hypomanic, or mixed episodes.
Clinical diagnosis using DSM-IV-TR criteria.
Cyclothymic disorder
Recurrent mood disturbances between hypomania and dysthymic mood.
Clinical diagnosis using DSM-IV-TR criteria.
Chronic psychosis (schizophrenia or delusional disorder)
Auditory hallucinations, thought disorder, delusions, demotivation, self-neglect, and reduced emotion.
Clinical diagnosis using DSM-IV-TR criteria.
Mood disorder due to substance abuse/alcohol abuse
Patients often report insomnia, nightmares, poor memory, and nervousness.
Clinical diagnosis using DSM-IV-TR criteria.
Depressive disorder, not otherwise specified
If the criteria for dysthymia, major depression, bipolar disorder, or any other mood disorder are not met.
Clinical diagnosis using DSM-IV-TR criteria.
Anxiety disorder
Excessive worry, muscular tension, fatigue, autonomic hyperactivity, and increased vigilance.Anxiety disorders are frequently comorbid with mood disorders. If the anxiety disorder is 'primary', which means it came before the mood disorder, then the mood disorder would be 'secondary'.
Clinical diagnosis using DSM-IV-TR criteria.
Obsessive-compulsive disorder
Repetitive patterns of behaviour; disturbing and intrusive thoughts; images or impulses that are generally seen by the patient as excessive, irrational, and ego-alien.
Clinical diagnosis using DSM-IV-TR criteria.

Dystonias

Athetoid or spastic cerebral palsy
Patients typically present with other signs of developmental delay from birth.
Cranial CT or MRI may reveal periventricular leukomalacia or evidence of cerebral anoxia or infarct.
Huntington's disease (HD)
Typically present with psychosis or mood disorder. Cognitive impairment or dementia may be prominent and seizures may also be present.Choreiform movements are more irregular and unsustained than dystonia, which is more sustained and stereotyped.
HD gene >40 trinucleotide CAG repeats.
Parkinson's disease (PD) or atypical parkinsonism
Typical features are bradykinesia, rigidity, and tremor.
Diagnosis is clinical.PET scan may show reduced dopamine uptake.MRI scan may show cerebral atrophy in advanced disease.
Wilson's disease
Patients may present with a history of liver disease.Detection of Kayser-Fleischer rings on slit-lamp examination, representing copper deposition on Descemet membrane on the cornea. This is virtually pathognomonic.
Abnormal LFTs.Serum ceruloplasmin is <20 mg/dL (<200mg/L); 24-hour urinary copper is >100 micrograms.
Psychogenic dystonia
Patients may present with an unusual pattern of dystonia and discrepancy between patient's disability and objective signs. Psychological comorbidity may be present.
Diagnosis is clinical.
Non-dystonic torticollis
A history or examination consistent with ocular motility problems, nuchal mass, atlantoaxial subluxation, or other structural cervical spine abnormality.
Cervical spine imaging may show skeletal pathology (e.g., nuchal mass, atlantoaxial subluxation, or other structural cervical spine abnormality).

Ectopic pregnancy

Miscarriage
Includes anembryonic gestation, threatened abortion, incomplete abortion, complete abortion, missed abortion.Often presents with vaginal bleeding in the first trimester, accompanied by abdominal discomfort secondary to uterine contractions.History may yield disappearance of pregnancy symptoms such as breast tenderness and nausea.
Ultrasound shows intrauterine pregnancy or products of conception.Pelvic examination may note dilation of the cervix, as well as presence of tissue at the cervical os.Consecutive serum chorionic gonadotrophin levels often do not rise appropriately (66% in 48 hours), and progesterone levels often <15.9 nmol/L (<5 ng/mL).
Acute appendicitis
Anorexia and periumbilical pain followed by nausea, RLQ pain, and vomiting.
Ultrasound sensitivity of 85% to 90% and specificity of 92% to 96%; may show appendix with outer diameter >6 mm, no compressibility, lack of peristalsis, or periappendiceal fluid.WBC count >10,000 cells/mm^3.
Ovarian torsion
Sudden onset, severe, unilateral lower abdominal pain that worsens intermittently over many hours.Peritoneal signs are often absent.
Ovarian enlargement secondary to impaired venous and lymphatic drainage is the most common sonographical finding in ovarian torsion.Absence of arterial blood flow may also be used for diagnostic purposes, but this is often absent in the early stages of torsion.
PID or tubo-ovarian abscess
Lower abdominal tenderness on palpation, adnexal tenderness, and cervical motion tenderness.May also have oral temperature >38.4°C (101°F) and abnormal cervical or vaginal discharge.
Although rare in pregnancy, can occur in the first 12 weeks of gestation before the decidua seals off the uterus from ascending bacteria.WBC count often >10,000 cells/mm^3.Ultrasound not used in uncomplicated PID, but is a valuable adjunct in diagnosis of tubo-ovarian abscess.
Ruptured corpus luteal cyst or follicle
Non-specific nausea, vomiting, low grade fever, and pelvic pain, which is often sharp, intermittent, sudden in onset, and severe.At times the ruptured cyst may lead to profuse bleeding and result in haemorrhagic shock.
Doppler ultrasonography usually diagnostic, especially when transvaginal and transabdominal modalities are used together.
Nephrolithiasis
Classically writhing in pain, pacing about, and unable to lie still, in contrast to a patient with peritoneal irritation, who remains motionless to minimise discomfort.Often presents with unilateral or bilateral flank pain.
Haematuria (presence of >1 RBC/hpf) and pyuria (>5 WBC/hpf on a centrifuged specimen) common.Due to potential risks to the fetus, the only imaging modalities used in pregnant women are ultrasonography (direct visualisation of the stone, hydroureter >6 mm in diameter, and perirenal urinoma suggesting calyceal rupture) and MRI (if ultrasound is non-diagnostic).
UTI
Dysuria with accompanying urinary urgency, frequency, and abdominal discomfort along the surface of the bladder.
May have pyuria (>5 WBC/hpf on a centrifuged specimen).Presence of nitrites is highly specific for a UTI, but its absence should not exclude the diagnosis.In all pregnant women with suspected UTI, urine culture must be obtained because the infection increases risk of pre-term labour and pregnancy loss.

Ehlers-Danlos syndrome

Marfan's syndrome
FHx of sudden collapse, aortic aneurysm, aortic dissection, and valve pathology suggestive.Marfanoid habitus is characteristic and necessary for diagnosis. Features include: high arched palate; arachnodactyly; pectus excavatum or carinatum; scoliosis; arm span to height ratio >1.05; tall stature with lower limb length (floor to pubis) to upper body (pubis to crown) ratio >0.89; foot length (heel to first toe) to height ratio >0.15; hand length (wrist crease to third finger) to height ratio >0.11. [18]Lens dislocation, neurological abnormalities of the pelvis and lower limbs suggesting peripheral nerve entrapment (dural ectasia), and signs of pneumothorax (tracheal deviation, decreased air entry on affected side) may be present.
Aortic regurgitation and aortic root dilation are common findings on echocardiogram; may also reveal ascending aortic dissection.MRI of the lumbar spine may show dural ectasia.Molecular analysis of peripheral blood sample shows fibrillin I and II abnormalities.Pneumothorax and emphysematous bullae on CXR may be noted.
Fibromyalgia
Chronic pain syndrome diagnosed by the presence of widespread body pain (front and back, right and left, both sides of the diaphragm) for at least 3 months in addition to tenderness (digital palpation at a force of about 4 kg) of at least 11 out of 18 designated tender-point sites. [25]
Diagnosis is clinical.
Chronic fatigue syndrome
Characterised by persistent fatigue and other associated symptoms (e.g., musculoskeletal pain, sleep disruption, memory impairments) lasting at least 6 months. The fatigue is not related to other medical conditions, disease processes, or identifiable biological causes. Sleep, rest, and activity restriction do not improve symptoms.Patients may present with a low-grade fever, tender lymph nodes, muscle pain/joint stiffness on palpation, tachycardia, hyperventilation, and/or orthostatic hypotension.
Diagnosis is clinical.
Loeys-Dietz syndrome
Autosomal dominant genetic syndrome that has many features similar to Marfan's syndrome. [26]Pronounced skeletal deformities have been reported in children. Key skeletal elements include club feet, scoliosis, upper cervical deformity, and knee or elbow hyperextensibility. Presence of hypertelorism, cleft palate, or bifid uvula should prompt referral to a geneticist. [26]
Genetic testing reveals mutations in the genes encoding transforming growth factor beta receptor 1 or 2.Aortic root dilation is a common finding on echocardiogram.
Thrombotic thrombocytopenic purpura
Neurological examination might reveal focal abnormalities, and presence of pallor (anaemia) and petechiae can support the diagnosis.
Examination of the peripheral smear is critical and shows evidence of microangiopathic haemolytic anaemia with fragmented RBCs (schistocytes) and thrombocytopenia.
Idiopathic thrombocytopenic purpura
Isolated thrombocytopenia in the absence of other causes; thought to be due to an autoimmune phenomenon. Typically found in middle-aged women, often with a preceding viral illness, who present with thrombocytopenia with or without bleeding.Physical examination is usually normal. Petechiae may be present on mucosal membranes or the lower limbs.
FBC and smear shows isolated thrombocytopenia.
von Willebrand's disease
Usually presents with mucocutaneous bleeding.
Diagnosis is based on various tests, including von Willebrand factor (VWF) antigen, VWF activity (ristocetin co-factor or collagen-binding assay), factor VIII assay, and VWF multimers.
Corticosteroid excess
One of the most common causes of poor wound healing; hx of chronic corticosteroid use usually present.
Diagnosis is clinical.
Porphyria cutanea tarda
Results from an acquired, substantial deficiency of uroporphyrinogen decarboxylase in the liver.Recognised by blistering and crusted skin lesions on the back of hands and other sun-exposed areas of the body. Other common features include skin fragility with minor trauma causing blister formation, hypertrichosis, skin hyperpigmentation, and dark or reddish urine.
High plasma and urine total porphyrins.
Epidermolysis bullosa
Inherited mechanical fragility of the skin and epithelial tissues. Presents as recurrent erosions, blisters, and scars.
Diagnosis is confirmed by immunofluorescence antigenic mapping performed on a cryopreserved skin biopsy specimen, obtained from a freshly induced lesion.
Vitamin C deficiency
Scurvy is a rare disorder, with epidemics typically affecting populations subject to famine or displacement during wartime.Most key clinical manifestations are related to impaired collagen synthesis. These include bleeding complications (spontaneous petechiae and ecchymoses), friable gingiva and loose teeth, bone pain, and joint effusions.
Low levels of serum, leukocyte, and whole blood ascorbic acid confirm the diagnosis.

Ehrlichiosis

Pneumonia, bacterial or viral
Cough is productive.
Chest x-ray usually shows areas of consolidation (increased radiodensity), whereas in human monocytotropic/monocytic ehrlichiosis (HME) and human granulocytotropic/granulocytic anaplasmosis (HGA), chest x-ray might show interstitial pneumonitis simulating a viral infection.Viral infections are ruled out based on specific laboratory tests (i.e., antigen detection, serology, PCR).
Gastroenteritides, bacterial or viral
Nausea, vomiting, and diarrhoea are more prominent.
Direct examination of stool may demonstrate polymorphonuclear neutrophils and/or blood.Stool cultures and antigen detection confirm diagnosis.
Cholecystitis
Right upper quadrant pain is usually localised.
Right upper quadrant abdominal ultrasound may show inflammation and dilatation of ducts in the area of the gallbladder.
Sepsis
There are no differentiating signs or symptoms.
Positive blood cultures.
Rocky Mountain spotted fever
Frequency of rash is much higher.
Positive PCR or immunofluorescence antibody assay specific for rickettsial DNA.
Thrombotic thrombocytopenic purpura
Thrombocytopenia and a purpuric rash.
Peripheral smears show schistocytes.Serum shows elevated lactate dehydrogenase.
Babesiosis
Jaundice is more frequent due to haemolysis.Can coexist with human granulocytotropic/granulocytic anaplasmosis (HGA) and/or Lyme disease. All 3 aetiological agents are transmitted by the same tick vector.
Diagnosed in the acute phase by observing typical intraerythrocytic parasites in peripheral blood smear.PCR is available at research laboratories and is positive for Babesia microti DNA/RNA.Serological diagnosis is possible in convalescent period. Antibodies against B microti present.
Malaria infection
Travel history to endemic areas. Presence of cyclical fevers.Jaundice is more frequent due to haemolysis.
Diagnosed in the acute phase by observing typical intraerythrocytic parasites in peripheral blood smear.
T-cell lymphoma
Lymphadenopathy is not short lived.
Circulating lymphocytes do not start decreasing by third week of illness.Tests for clonality: T-cell receptor re-arrangements. However, in sporadic cases, lymphocytosis is severe enough to cause false-positives with this test, and follow-up testing is indicated.
Typhoid infection
May be difficult to distinguish; however, gastrointestinal symptoms are more frequent.
Blood and/or stool cultures positive for Salmonella enterica serovar S typhi or S paratyphi.
Lyme disease
Presence of erythema migrans.Can coexist with human granulocytotropic/granulocytic anaplasmosis (HGA) and/or babesiosis. All 3 aetiological agents are transmitted by the same tick vector.
Serological diagnosis is possible in convalescent period. Antibodies against Borrelia present.Western immunoblotting shows presence of Lyme-specific IgM and IgG.PCR positive for Borrelia.

Elder abuse

Dementia
Patients may present with delusions or paranoia and failure to thrive.
Further evaluation with home health agency and psychiatrist involvement may assist in the diagnosis.
Falls in the elderly
Identifying the circumstances surrounding the fall and the symptoms associated with the fall helps to determine the underlying cause.
Evaluation of neurological issues and other sensory systems can help with the evaluation of recurrent falls.
Medicine non-compliance
Symptoms of underlying illness re-emerge (e.g., increased BP, serum lipids, blood glucose).
Previous history suggestive of non-compliance is helpful in delineating this issue.
Substance abuse
Behavioural symptoms are caused by the direct physiological effects of substance use or as a result of substance withdrawal.
Urine and blood testing for illicit substances.
Depression
May present with severe cognitive disturbance (memory deficits) as a result of the depression.
Further evaluation with home health agency and psychiatrist involvement may assist in the diagnosis.It is recommended that clinicians use specific diagnostic testing for older people (e.g., the Geriatric Depression Scale) [Geriatric Depression Scale] or for older people with cognitive impairment (e.g., the Cornell Scale for Depression in Dementia). [Cornell Scale for Depression in Dementia]

Electrical injury

Cardiac arrest
Hx of cardiac disease or FHx of sudden cardiac death.
Elevated cardiac enzymes. However, elevated CK 5x normal may suggest compartment syndrome with rhabdomyolysis in patient with electrical injury.
Ventricular arrhythmia
Hx of cardiac disease, in particular recent cardiac ischaemia.
ECG - abnormal rhythm.
Illicit drug use
Hx of illicit drug use.Track marks.Altered mental status.
Urine toxicology screen for illicit drugs.
Acute stroke
Hx of hypertension or vascular disease.Limb hemiparesis, cranial nerve abnormalities, or speech changes.
CT brain - haemorrhage or areas of ischaemia.
Subarachnoid haemorrhage
Hx of known cerebral aneurysm or risk factors for cerebral aneurysm (e.g., polycystic kidney disease).Severe headache.
CT brain - subarachnoid blood.Lumbar puncture - elevated RBC count with xanthochromia.
Generalised seizures
Hx of seizures or risk factors for seizures (e.g., alcohol abuse, intracranial lesion).Witnessed tonic-clonic movement.Tongue biting.Urinary or faecal incontinence.
EEG - epileptiform discharges.

Empyema

Pneumonia
No differentiating signs or symptoms.
CXR: consolidation without associated effusion.
Uncomplicated parapneumonic effusion
No differentiating signs or symptoms.
Pleural fluid: serous in appearance.Gram stain and culture: negative.Pleural fluid pH: >7.2. [2]
Lung abscess
Cough productive of foul-smelling sputum.
CXR: cavitating lung lesion with air-fluid level.Contrast-enhanced thoracic CT: demonstrates thick-walled irregular cavity with indistinct boundary between abscess and normal lung, vessels may be visible passing through the abscess. [19]
Malignant pleural effusion
Longer history of symptoms.Past medical history of cancer which may be known to be metastatic.Caution is required as malignancy and infected pleural effusions can co-exist.
Pleural fluid pH in both malignant and infected effusions: <7.2.Thoracentesis pleural fluid cytology: may demonstrate malignant cells.CXR: may demonstrate primary tumour.Thoracic ultrasound: may demonstrate pleural thickening and nodularity.CT scan: findings suggestive of malignant pleural effusion are pleural thickening extending onto the mediastinum, circumferential pleural thickening, nodularity, and pleural thickening >1 cm.
Chylothorax
No infective symptoms.
Pleural fluid: remains milky in appearance when centrifuged, in empyema debris settles out on centrifuge.Pleural fluid: triglycerides >110 mg/dL, levels of 50 to 110 mg/dL should be followed by lipoprotein analysis for the detection of chylomicrons.
Oesophageal rupture
Recent history of vomiting or retching. [1]
Pleural fluid: contains food debris and amylase of salivary origin.CXR: may show hydropneumothorax.CT scan: may demonstrate oesophageal wall thickening, mediastinal widening, and a pleural space gas-liquid level.Oral contrast-enhanced CT: may show contrast within the mediastinum.Oesophagram with gastrograffin: reveals the location of rupture.
Haemothorax
History of anticoagulation or bleeding diathesis.Close temporal relationship with thoracic trauma or iatrogenic intervention in the pleural space.Caution is required as a haemothorax may become secondarily infected.
Pleural fluid: frankly bloody.Pleural fluid haematocrit: >50% of peripheral blood haematocrit.

Encephalitis

Aseptic meningitis
Headache, neck stiffness, and fever with no altered mental status (maybe mild somnolence) or focal neurological signs.Frequently meningitis and encephalitis co-exist (meningoencephalitis).
MRI evidence of meningeal enhancement, with no evidence of brain parenchymal involvement.
Encephalopathy (toxic/metabolic)
A multitude of metabolic factors and remote infections can cause brain parenchymal dysfunction without structural damage to the brain.Frequently encountered in hospital/nursing-home settings.Altered mental status and even focal neurological signs (hypoglycaemia) can be seen with both conditions, and there are no specific clinical differentiating features.
Normal CSF analysis, normal MRI, EEG-diffuse slowing, triphasic waves.
Status epilepticus
There are no specific clinical differentiating features, and status epilepticus is not uncommonly seen in patients with encephalitis so can be considered a clinical feature of this disease.In cases that are clearly not due to encephalitis (MRI, CSF negative), the patient frequently has a known seizure disorder with sub-therapeutic levels of medications.
EEG - evidence of ongoing seizure activity.
CNS vasculitis
There are no specific clinical differentiating features. Headaches and focal neurological signs can be seen.
Differentiated by MRI, angiography, and biopsy.MRI - evidence of multiple small strokes, usually cortical.Angiography - can be normal, but frequently a typical angiographic appearance of multi-segment narrowing/beading of the vessels is noted.Definitive diagnosis sometimes requires brain and meningeal biopsy, which will show evidence of inflammation (i.e., presence of inflammatory cells such as lymphocytes in the vessel wall and surrounding the blood vessel, along with structural alterations of the involved vessels).
Pseudomigraine with pleocytosis
Acute confusion, psychosis, and focal neurological deficits in association with migraine headache is seen in some migraine patients, [22] and in familial hemiplegic migraine. [23] These are suggestive of but not specific to migraine. [9]
CSF - elevated WBC count with no evidence of infection.
Malignant hypertension
High blood pressure, headaches, altered mental status, and visual symptoms can be seen.
Elevated BP (usually >220/110 mmHg). But may be sudden acute elevations even at lower blood pressure.Differentiated by fundoscopy, CT, and MRI.Fundus examination - papilloedema and haemorrhage.CT usually normal, but occasionally hypodense lesions seen over occipital lobes.MRI: T2 and fluid attenuated inversion recovery (FLAIR) hyperintense lesions over the occipital lobes (usually asymmetric). Increased diffusion on diffusion-weighted imaging (with apparent diffusion coefficient maps showing increased diffusion) is also seen. The term 'posterior reversible leukoencephalopathy' is also used to describe the MRI changes.
Intracranial tumours and cysts
There are no specific clinical differentiating features.A variety of clinical presentations, such as headache worse on awakening, altered mental status, seizures, and focal neurological deficits, are seen with intracranial neoplasms.
CT and MRI imaging of the brain (preferably MRI) can help to diagnose these conditions. Biopsy - required in some cases to make a definitive diagnosis. Biopsy results are specific to the underlying tumour.
Intracranial bleeds
There are no specific clinical differentiating features. Headache, altered mental status, seizures, and focal neurological deficits can be seen.
CT and MRI can clearly demonstrate acute intracranial bleeds. In subarachnoid haemorrhage, LP may show xanthochromia and no change in the number of RBC from tube 1 to tube 4.
Traumatic brain injury
A history of head injury is frequently obtained, but can be unavailable in someone who is found unresponsive.Headache, varying degrees of altered mental status, and focal neurological findings can be seen.There are no specific clinical differentiating features.
CT and MRI will reveal various intracranial bleeds that are associated with head injury; concussions have normal imaging findings; diffuse axonal damage can be seen as signal abnormality in MRI images.
Ischaemic strokes
There are no specific clinical differentiating features.Sudden onset of focal neurological deficits, altered mental status, seizures, and headaches.Certain strokes, such as those involving the posterior cerebral artery, basilar artery, and anterior cerebral artery, can present with an encephalopathic clinical picture.It is important to note that ischaemic stroke can also occur as a complication of some cases of encephalitis.
CT scan - low attenuation in the involved areas.MRI - diffusion-weighted imaging evidence of decreased diffusion is characteristic of acute ischaemic stroke. FLAIR and T2 hyperintense lesions are seen in subacute cases.
Mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS)
There are no specific clinical differentiating features. Hearing loss, encephalopathy, seizures, stroke-like episodes, and presence of lactic acidosis are characteristic clinical features.
Lactate - elevatedMRI - T2 hyperintense signal in territory not conforming to major vascular regions. Diffusion weighted imaging evidence of increased diffusion.Genetic test - mitochondrial DNA point mutations (A3243G mutation in 80% of cases).Muscle biopsy - ragged red fibres on modified Gomori trichrome stain.
Mycoplasma pneumoniae infection
Hx cough, fever, dyspnoea, sputum production. Elevated respiratory rate, crackles, and dullness to percussion may be found on examination. [24]
Chest x-ray may show consolidation. Blood culture or PCR (blood) may detect Mycoplasma pneumoniae.
Human granulocytic anaplasmosis
Hx tick bite, fever, and chills. Rash may be present on examination. [25]
Peripheral blood smear may show intragranulocytic inclusions. Indirect fluorescent antibody assay may be positive for Anaplasma pagocytophilum. [25]
Progressive multifocal leukoencephalopathy
Hx immunosuppression (e.g., AIDS, organ transplant). May have limb weakness, gait disorders, speech disorder, or visual impairment.Physical examination may reveal ataxia, cranial nerve palsies, paralysis of limbs, and speech disturbances. [26]
CSF PCR may show JC virus.
Inborn errors of metabolism
Hx parental consanguinity, early neonatal death, maternal acute fatty liver of pregnancy and HELLP syndrome (elevated liver enzymes and low platelets) in pregnancy. May be lethargic and irritable with poor feeding. Physical examination may reveal jaundice, cataracts, hepatosplenomegaly, abnormal muscle tone, dysmorphism (e.g., coarse facial features), and abnormal body odour. May present with life-threatening encephalopathy. [27] [28]
Serum ammonia may be elevated (urea cycle defect, organic acidaemias). Arterial blood gas can show a metabolic acidosis with elevated anion gap. Urine orotic acid is low in carbamyl phosphate synthetase deficiency and elevated in ornithine transcarbamylase deficiency. [28]
Bacterial/fungal meningitis
Hx headache, neck stiffness, photophobia, and fever.Hx immunosuppression may be present in fungal meningitis.Physical examination may reveal fever, neck stiffness, and focal neurological abnormalities.
Bacterial meningitis: CSF shows elevated WBC often with neutrophil predominance, elevated protein, and low glucose. Gram stain and PCR may reveal the causative organism. [29] CSF culture may demonstrate fungal growth.

Endometrial cancer

Endometrial hyperplasia
Commonly presents with abnormal uterine bleeding. [15]If woman is pre-menopausal, she may have a history of irregular heavy periods or amenorrhoea. If woman is post-menopausal, history and physical examination are indistinguishable from endometrial cancer.
Endometrial biopsy is the only test that may differentiate endometrial hyperplasia from cancer. [15]Even then, endometrial cancer may be present in up to 30% of cases when the initial diagnosis is hyperplasia with atypia. [16]
Endometrial polyp
Usually asymptomatic, but when polyps are the cause of abnormal vaginal bleeding, the history is no different from cancer.Occasionally, pelvic examination reveals an exocervical polyp.
Transvaginal ultrasound may show thickened endometrial lining that is not uniform.Saline infusion sonohysterogram demonstrates polyps well.MRI will also demonstrate polyps, but is not usually necessary.
Endometriosis
More common in younger, pre-menopausal women.Pelvic pain, dyspareunia, and painful defecation are key features of this condition.Physical examination will detect tenderness and may detect typical nodularity.
Pelvic ultrasound may show endometrioma.If a tissue biopsy is obtained, it shows characteristic benign endometrioid glands associated with changes of haemorrhage including haemosiderin-laden macrophages.
Cervical cancer
Patients are typically younger, may be multi-parous, and usually have not had a cervical Pap smear for a long time.Vaginal bleeding is usually provoked (e.g., by sexual intercourse).Sometimes, there is associated offensive discharge.Physical examination shows an abnormal-looking cervix, and there may be an exophytic cauliflower growth.
Colposcopy may show a mass lesion on the cervix.Cervical biopsy and histopathology will show invasive squamous cell carcinoma, often associated with an in-situ component.
Pyometria
Commonly associated with cervical stenosis, and there may be a history of recent cervical surgery.Patients may be febrile and have other symptoms of sepsis.Physical examination may reveal an enlarged, tender uterus.Can be associated with an occult endometrial carcinoma, especially in older women.
Pelvic ultrasound will show intra-uterine collection of fluid.Cervical dilatation will lead to pus drainage from the cervix.

Endometriosis

Adenomyosis
Symptoms may be identical to those of endometriosis.
Pre-operative MRI findings may show diffuse or focal widening of the junctional zone (inner myometrium), islands of endometrial tissue or cystic dilation of glands or haemorrhage, linear striations radiating out from the endometrium into the myometrium, mass within the myometrium (adenomyoma).Laparoscopy may reveal a normal pelvis or concurrent endometriosis.Histopathological evaluation of the uterus after hysterectomy shows endometrial glands/stroma in the myometrium.
Interstitial cystitis
Symptoms primarily localised to the bladder, such as urinary frequency and urgency. Patients complain of pain with a full bladder that is relieved upon voiding.Diffuse chronic pain and dyspareunia are common and often indistinguishable from endometriosis.
Cystoscopy with hydrodistention shows glomerulations (pinpoint mucosal haemorrhages) and Hunner ulcers as distention medium is released.Potassium chloride sensitivity test: after instilling a dilute solution of potassium chloride into the bladder with a catheter, the patient will note a change in urinary urgency and frequency scores.
Pelvic inflammatory disease
Fever, nausea, acute pain along with malodorous vaginal discharge and cervical motion tenderness/adnexal tenderness is typical for acute PID.Chronic PID may be indistinguishable from endometriosis.
Cervical cultures for Neisseria gonorrhoea or Chlamydia trachomatis may be positive.Pelvic ultrasonography may show complex adnexal masses as distinguished from homogeneous, low-level echoes typically seen with endometrioma.
Irritable bowel syndrome
Change in bowel habits (alternating constipation and diarrhoea; bloating) may help differentiate. Dyschezia more typical of endometriosis.
Diagnosis is usually clinical and based on an absence of ultrasound, MRI or laparoscopic findings of endometriosis.
Ovarian cyst (benign)
May be asymptomatic with an incidental pelvic mass or present with acute rather than chronic pain.
Transvaginal ultrasound (TVUS): enlarged ovary with a simple or complex cystic structure emanating from the ovary as distinguished from homogeneous, low-level echoes typically seen with endometrioma. Ultrasound is ideal for differentiating liquid from solid material.
Ovarian cancer, epithelial
Typical symptoms represent advanced-stage cancer, and include weight gain despite lack of appetite, increased abdominal girth and altered bowel habits.Endometriosis may be an uncommon risk factor for developing epithelial ovarian cancer.
TVUS: complex adnexal mass (solid and cystic) with multiple loculations or thick septa; ascites. Most patients present with advanced-stage disease.Histopathology: there are many cell types and various stains can be used to verify/differentiate.
Pelvic floor tension myalgia
May be unable to differentiate clinically.Clinically patients have chronic pelvic pain and dyspareunia (or inability to have intercourse due to spasm and pain).An experienced clinician can elicit focal spasm and tenderness on pelvic and rectovaginal examination.
No diagnostic test available. Lack of positive findings on other investigations.
Neuropathic pain
Burning, shock-like pain associated with paraesthesia or dysaesthesia.
No diagnostic test available. Lack of positive findings on other investigations.
Uterine fibroids
Many are asymptomatic, but often present with heavy and/or irregular menstrual bleeding.Pelvic examination may show an enlarged, nodular pelvic mass that can vary in size and shape.
TVUS: concentric, solid, hypoechoic (dark) mass or masses within the endometrium (sub-mucosal), myometrium (intramural) or external (sub-serosal). Small fibroids may be isoechoic, but if calcified, fibroids can also appear hyperechoic (bright).

Enuresis

Congenital abnormality of the urinary tract (e.g., ectopic ureter, ureterocele, and urethral valves)
Urinary tract infections, hydronephrosis, and daytime voiding dysfunction are clinical features differentiating from enuresis.
Abdominal ultrasound; voiding cystourethrogram.
Constipation
Faecal incontinence, hard stools, and blood per rectum suggest primary constipation as a possible cause for urinary symptoms.
Faecal markers (radio-opaque markers that are given on 3 consecutive days to evaluate constipation) and kidney, ureter, bladder (KUB) x-ray, or ultrasound scan will demonstrate constipation.
Diabetes
Glycosuria and polyuria. May also present with weight loss and polydipsia, which are distinguishable clinical features.
Urinalysis; fasting serum glucose; HbA1c.
Detrusor overactivity
Daytime urinary frequency, urgency, and possibly daytime incontinence.
Urodynamics; bladder ultrasound may demonstrate a thick bladder wall.
Detrusor areflexia
Daytime urinary infrequency and overflow incontinence may be distinguishing clinical features; most patients with enuresis do not have daytime symptoms.
Urodynamics; bladder ultrasound may demonstrate thin bladder wall.
Emotional disturbance
Depression and/or defiant activity may be overriding features together with urinary symptoms; not always easy to distinguish as may occur simultaneously.
Diagnosis is clinical.
Neurological disorder leading to voiding dysfunction (i.e., spina bifida; epilepsy)
Daytime voiding dysfunction primarily, as opposed to nocturnal symptoms. In spina bifida there is sacral deformity. Epilepsy is usually defined by occurrence of at least 2 unprovoked seizures and may be associated with incontinence.
Tests depend on underlying condition, and diagnosis may be clinical. EEG may show typical abnormalities in epilepsy. Spina bifida may be shown by x-ray, CT, or MRI scan.
Urinary tract infection
Fever, dysuria, and abdominal pain.
Urinalysis and urine culture will be positive for culprit micro-organisms.

Epicondylitis

Radial tunnel syndrome
Radial tunnel syndrome is also associated with repetitive activities. [45]A history of acute trauma may be elucidated during the initial patient interview.Patients will experience pain localised over the radial neck approximately 4 finger-breadths distal to the lateral epicondyle.This pain may be exacerbated by pronation of the forearm with the elbow extended, resisted supination, and extension of the long fingers. [45] [46]
Both radial tunnel syndrome and lateral epicondylitis are primarily a clinical diagnosis.Physical examination will assist in differentiation by location of pain and exacerbation of symptoms with long finger extension.
Radial capitellar plica
Differentiated from lateral epicondylitis by passive flexion of the elbow while pronating and supinating the forearm. [34]This manoeuvre produces snapping or popping at the radial head. The snapping with this forearm manoeuvre does not occur with epicondylitis, and is highly suggestive of a plica.A history of trauma along with this finding on examination is highly suggestive.
Usually differentiated from epicondylitis by findings on clinical examination.
Osteoarthritis
Osteoarthritis of the elbow is usually associated with a previous history of traumatic injury.Patients with osteoarthritis will report chronic pain, stiffness, mechanical symptoms, and weakness. [47]
Radiographic studies in early disease may depict a preserved joint space in the radial capitellar and ulnohumeral joints. Advanced disease may demonstrate a complete loss of joint space and the presence of intra-articular loose bodies. [48]
Primary ligamentous instability
Damage to the ulnar collateral ligament may produce symptoms similar to those of medial epicondylitis due to repetitive valgus loading of the elbow. [18]On physical examination, patients with ulnar collateral ligament injury will have valgus instability with the elbow at 30 degrees of flexion. [18]
Radiographic studies of the elbow may demonstrate an avulsion fracture of the sublime tubercle, as well as attenuation versus tear of the ligament when MRI is employed. [49]
Cubital tunnel syndrome
Patients with ulnar nerve entrapment (most commonly at the cubital tunnel posterior to the medial epicondyle) will report a history of medial-sided pain, numbness in the ulnar distribution, and hand weakness. [18] [50]During physical examination a positive Tinel's sign may be induced above or below the medial epicondyle. This finding is consistent with ulnar nerve entrapment at the elbow. [18]
Primarily differentiated by physical examination.Patients with findings consistent with ulnar nerve entrapment may benefit from an EMG and nerve conduction evaluation to determine the extent of nerve damage and assess the zone of compression. [51]

Epidermolysis bullosa

Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma)
Blistering during early infancy may be similar to that of epidermolysis bullosa (EB), although usually the skin is not markedly fragile.The oral cavity is uninvolved.In older children, arm skin develops characteristic carpet-like thickening and scale, most pronounced within the antecubital fossae.
Transmission electron microscopy demonstrates intra-epidermal dysadhesion of keratinocytes.
Congenital porphyrias
Some porphyrias may, like some types of EB, be associated with vesiculation or blistering of the skin with milia, although mechanical fragility is usually absent.In one type, erythropoietic protoporphyria, a stinging or burning sensation, particularly on the face, follows brief (i.e., minutes) exposure to sunlight.With time, cobblestone-like changes and scarring develop on the face.
Specific urinary porphyrin levels are elevated in patients who have a congenital form of porphyria.
Cutaneous absence of skin (aplasia cutis)
Infants with aplasia cutis, in the absence of EB, usually have wedge-shaped depressed skin areas on the scalp.Blisters and mechanical fragility are absent.In contrast, when aplasia cutis occurs in a patient with EB (Bart's syndrome), these lesions are usually on the feet, ankles, and wrists. [36]
No differentiating test is usually performed.A skin biopsy may be obtained to definitively confirm the diagnosis, but clinical findings alone are usually adequate.
Immunobullous diseases (e.g., pemphigoid, pemphigus, EB acquisita, linear IgA dermatosis)
Rare in newborns and infants.Most lack clinically significant mechanical fragility or any of the other skin findings (milia, nail dystrophy, scarring) that are characteristic of inherited EB.Other family members are usually unaffected.
Direct immunofluorescence is positive in all immunobullous diseases, with patterns indicative of specific diseases.Bullous pemphigoid skin has IgG and C3 along the dermo-epidermal junction (DEJ).Linear IgA dermatosis (chronic bullous dermatosis of childhood) has only IgA in linear array along the DEJ.EB acquisita has multiple immunoglobulins and C3 along the DEJ.Pemphigus has IgG and C3 in an intercellular pattern within the epidermis.Sera from these patients contain specific auto-antibodies having identical binding patterns on normal human skin or monkey oesophagus.
Congenital or acquired viral infections (varicella, herpes simplex)
More commonly vesicular rather than bullous.Not associated with other skin findings typically seen in EB.The skin is not mechanically fragile.Maternal history may be positive for infection during pregnancy.
Tzanck preparation of the blister fluid demonstrates multi-nucleate giant cells.Characteristic cytopathic changes are seen in viral cultures incubated with blister fluid.
Bullous impetigo
Uncommon in early infancy.Usually a very localised eruption.Tense blisters arise on reddened skin.Typical sites include the groin, trunk, and umbilicus.Ruptured lesions are covered with honey-coloured crusting.The skin is not mechanically fragile.
Bacterial culture of blister fluid reveal Staphylococcus aureus.
Staphylococcal scalded skin syndrome
Occurs in infants and small children.Usually adjacent to a site of skin infection, such as the ear canal or nares.Erosions arise on reddened skin, most notably on the face and upper chest.Blisters are conspicuously absent.The surrounding skin appears scalded and the surface can be easily peeled away with gentle lateral traction.
Skin biopsy reveals superficial cleavage just beneath the level of the stratum corneum.S aureus can be cultured from the adjacent infected skin.
Bullous mastocytosis
Localised tense blisters or vesicles arise on normal-appearing skin or on firm dermal plaques or nodules.Lesions may sometimes be induced by gentle stroking of the skin (Darier's sign).Milia are absent.The lesions are usually pruritic.Family history is negative.
Skin biopsy reveals dense collections of mast cells within the dermis, as well as within the blister cavity.
Other genodermatoses (e.g., pachyonychia congenital, Hay-Wells syndrome, acrodermatitis enteropathica, ichthyosis bullosa of Siemens, and incontinentia pigmenti)
Very rarely these diseases may present with vesicles or blisters.Each of these, however, has other clinical findings that permit them to be distinguished from inherited EB.
Each of these entities has distinguishing skin biopsy findings.Low serum zinc levels are characteristic of acrodermatitis enteropathica.
Lichen planus
The non-bullous skin lesions in patients with 2 rare dystrophic EB subtypes (pretibial dystrophic EB [DEB]; DEB pruriginosa) may resemble those of lichen planus (violaceus papules or small plaques).Buccal white patches (Wickham striae) typical of lichen planus, not EB.Patients with lichen planus often have associated nail changes (pterygium).
Skin biopsy reveals distinctive routine histological features, including band-like (lichenoid) infiltrate of lymphocytes along the DEJ, enlargement of the granular layer within the epidermis, and saw-toothed epidermal hyperplasia.

Epidural abscess

Epidural haematoma
Spontaneous spinal haematoma is rare, with an annual incidence of about 1 person per 1 million population. Rarely presents with fever, but pain and neurological signs are common. Related to the fragility of the epidural venous plexus, spinal epidural haematoma is seen more often after minor trauma and in males.
MRI shows low signal on T1 and bright on T2, with a few areas of T1 hyperintensity mixed within in the early phase. The lesion can be isointense to adjacent cord immediately after onset.
Multiple sclerosis
Variable presentation with multiple episodes. Can present with sudden neurological deficit, but rarely with fever or back pain. Common symptoms include progressive limb weakness, gait difficulty, ataxia, loss of balance, and paroxysmal vertigo.In the setting of acute paraparesis, visual symptoms (visual loss) may be present (neuromyelitis optica [NMO]). Patients may have optic disc atrophy.
Brain MRI typically shows areas of demyelination.CSF examination may show raised IgG and oligoclonal banding.Visual evoked potentials are most commonly abnormal, with somatosensory and auditory evoked potentials less so.Patients with NMO may show NMO-IgG seropositivity.
Malignant spinal cord compression
Clinical presentation may be similar.Patients may have hx of cancer or show signs of malignant disease (e.g., weight loss).
MRI shows spinal neoplasm.
Intervertebral disc herniation/compression
Patients typically present with chronic back pain and sometimes only leg pain. Neurological deficit is absent.
ESR, CRP, and FBC are typically normal.MRI shows disc compression or herniation.
Meningitis
Clinical presentation may be similar (with meningismus, malaise, and fever) but with less focal pain or spasm, and few radicular signs. Patients typically have moderate encephalopathy.
Imaging is negative for focal collections; may show diffuse dural enhancement. [28]
Transverse myelitis
Interval from pain onset to paralysis is often 1 day or less. Most patients are afebrile.
CSF analysis shows pleocytosis with a few lymphocytes and increased total protein.Imaging is often negative in early stage or may show focal cord T2 signal change without enhancement at the appropriate level.

Epiglottitis

Peritonsillar abscess
Bulging peritonsillar mucosa with marked unilateral tonsillar displacement and concomitant uvular deviation.
CT may show a hypodense fluid collection with rim enhancement.
Tonsillitis
Erythema of tonsils.
Lateral neck radiograph will be normal.
Foreign body aspiration
There may be no difference in signs and symptoms. Usually, the health professional may be able to elicit a history of a potential foreign-body aspiration.
Foreign body seen on imaging studies. Radiolucent objects may be missed. If suspicious of an aspirated foreign body, direct laryngoscopy and bronchoscopy is imperative.
Retropharyngeal abscess
This cannot be accurately differentiated by symptomatology or physical examination findings, which can be highly variable. All the spaces in the neck are interconnected; hence a severe infection in one fascial plane can lead to infection in other planes.
Lateral neck radiograph: may see a bulge of the retropharyngeal space on a lateral neck radiograph.CT scanning will demonstrate a retropharyngeal abscess.Direct visualisation by laryngoscopy may show bulging of the retropharyngeal space and the absence of epiglottitis.
Laryngotracheobronchitis
Stridor and barky cough, drooling, or tripod positioning.
Lateral neck radiograph will reveal classically appearing steeple sign of the subglottis.
Diphtheria
Pharyngeal membranes with diphtheria.
Direct visualisation examination. Microbiology assay positive for Corynebacterium diphtheriae.

Epistaxis

Haemoptysis
Patients with haemoptysis may have other respiratory signs and symptoms, such as cough, dyspnoea, wheeze, abnormal breath sounds on chest auscultation.
Usually only an initial confusion and clinically apparent after a more thorough patient examination.Chest x-ray or CT may be abnormal in patients with haemoptysis. Some bleeding sources require bronchoscopy for identification (e.g., pulmonary blood vessel that cannot be seen on imaging).
Haematemesis
Patients with haematemesis more likely to have other GI signs and symptoms, such as abdominal pain, melaena, history of peptic ulcer disease.
Usually only an initial confusion and clinically apparent after a more thorough patient examination.Upper GI endoscopy helpful in detecting bleeding source.

Equinovarus foot deformity

Metatarsus adductus
While the forefoot is adducted, the heel is neutral or slight valgus without equinus.
Usually not needed, but if underlying anomalies are suspected or when assessing an older child, x-rays can be obtained. These demonstrate a normal hindfoot and medial deviation of the metatarsals at the tarsometatarsal joint.
Skewfoot
Forefoot adduction with the hindfoot in valgus. No equinus deformity.
Standing x-rays demonstrate an increased angle formed by lines drawn through the calcaneus and talus on anteroposterior views. The navicular is displaced laterally instead of medially on clubfoot x-rays.
Calcaneovalgus or talipes calcaneal valgus
The foot is in maximum dorsiflexion at birth (the foot is in contact with the anterior tibia.) The heel is valgus. The deformity can usually be brought to a neutral position.
X-rays are not usually necessary as long as the examination can differentiate this from a vertical talus.
Vertical talus
The foot has the classic appearance of a 'Persian slipper' or rocker-bottom deformity. The heel cord is in fixed equinus as in clubfoot, but the heel in vertical talus is in valgus with the forefoot dorsiflexed at the midtarsal joints.
X-rays to include a maximum plantar flexion lateral view demonstrate a vertically oriented talus with no reduction of the dorsally dislocated forefoot on the talus during plantar flexion.

Erb's palsy

Clavicle or humeral fracture
Fractures can be associated with brachial plexus birth palsy (BPBP) but may be exclusive.Pseudoparalysis, which is a voluntary restriction or inhibition of motion not due to actual muscular paralysis, may appear clinically similar to BPBP.Crepitance will be noted at the fracture site, and return of normal function will be rapid (2-3 weeks) if no nerves have been injured.
Radiographs are diagnostic of fractures in this area.
Septic arthritis of the shoulder or proximal humeral osteomyelitis
Paralysis developing late (not present at birth) should be suspected as possible infection.Pain with movement of the shoulder is suggestive of infection, although it could also be suggestive of fracture.
Laboratory tests (full blood count with differential, erythrocyte sedimentation rate, and c-reactive protein) may suggest infection. Ultrasound or MRI will confirm effusion or bony involvement. Bone aspiration: positive culture is diagnostic of osteomyelitis.
Spinal cord or brachial plexus tumour
Paralysis developing after birth without signs of infection or with supraclavicular mass is suggestive of a tumour.
Imaging (MRI or CT scan) is diagnostic of spinal cord or brachial plexus tumours.
Parsonage-Turner syndrome
Patients presenting with brachial plexus dysfunction after a viral illness may have this syndrome.Paralysis develops suddenly after a period of shoulder pain and is unrelated to birth.
No differentiating tests are available because this is a diagnosis of exclusion. MRI of the cervical spine and shoulder and EMG nerve conduction studies of the affected extremity may be performed to localise possible site of injury with BPBP and to help to rule out other causes of sudden paralysis.

Erectile dysfunction

Premature ejaculation
Ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners. [51]
There are no distinguishing tests.
Priapism
A pathological condition of a penile erection that persists beyond or is unrelated to sexual stimulation, considered a medical/surgical emergency. [52]Persistence of an erection beyond 3 hours is considered significant symptom.Can be associated with tissue ischaemia.
There are no distinguishing tests.

Erythema infectiosum

Rubella
Typically, non-specific exanthem of rose-pink macules that spread cephalocaudally.Joint involvement is common.Tender cervical, occipital and/or posterior auricular lymphadenopathy is common. [10]
Serology shows presence of anti-rubella IgM or a 4-fold increase in anti-rubella IgG antibodies. [10]
Measles infection
Prodrome typically includes cough, coryza and conjunctivitis.There is an exanthem consisting of grey-white papules on the buccal mucosa (Koplik's spots) during the prodrome.The exanthem is an erythematous maculopapular eruption that spreads cephalocaudally and usually begins to clear within 1 week. [10]
Virus isolation can be obtained from a nasopharyngeal swab for viral culture.Serological assay for measles IgM is also available. [10]
Roseola infantum
Typical prodrome of sudden high fever that lasts for 3 to 5 days.Non-specific exanthem appears at the time of defervescence.The disease usually affects younger children (6 months to 3 years) than erythema infectiosum. [11]
Serological studies and PCR are all available to identify human herpesvirus type 6.Culture may be available but is rarely necessary. [11]
Scarlet fever
Typically preceded by pharyngitis and fever as opposed to the relatively asymptomatic prodrome of erythema infectiosum.The eruption associated is papular (a sandpaper texture) and spreads centripetally.Other cutaneous findings include petechial streaks in skin folds (Pastia's lines) and circumoral pallor.Mucosal signs include exudative pharyngitis and a white or beefy red tongue.Rash usually followed by desquamation. [12]
Cultures of oropharynx usually reveal the aetiological organism, Streptococcus pyogenes.Anti-steptolysin O (ASO) titres and anti-deoxyribonuclease-B titre (anti-DNase-B) may be helpful in the diagnosis as well. [12]
Erysipelas
Involved area usually a unilateral plaque as opposed to the bilateral macular cheek erythema seen in erythema infectiosum.Rash commonly warm, tender and indurated.Regional lymphadenopathy is typical. [13]
Occasionally, a left shift and elevated leukocyte count will be seen.Cultures of the affected area rarely yield the aetiological organism, Streptococcus pyogenes, but ASO titres and anti-DNase-B may indicate cutaneous infection. [13]
Drug hypersensitivity
History and temporal association with a causative pharmacological agent frequently identified.May be associated with a generalised maculopapular eruption.
No specific tests.
Systemic lupus erythematosus
Persistence of cutaneous and systemic symptoms with multi-organ involvement.The classic malar eruption of SLE involves the nasal bridge as opposed to the rash of erythema infectiosum.
Positive ANA titres and pathological examination of skin biopsy will differentiate lupus from erythema infectiosum.
Juvenile dermatomyositis
Characterised by progressive weakness rather than true arthritis as seen in erythema infectiosum.Calcinosis is a feature not seen in erythema infectiosum.The eruption of dermatomyositis often involves the face and eyelids but often has scale, in contrast to erythema infectiosum.Photo-sensitivity, nail fold telangiectasias and a scaling eruption over the knuckles, are highly characteristic of dermatomyositis.
Elevated serum CK, aldolase, LDH and positive serum ANA often seen in dermatomyositis.Skin biopsy can also help differentiate these 2 entities.

Erythema multiforme

Urticaria
Giant urticaria can be annular with central clearance, but central blistering and target lesions will be absent. While urticaria may recur, resolution of lesions in 24 hours is the norm, but virtually never occurs in EM. Daily new lesions occur in urticaria, but not in EM after the first 72 hours. [2]
Dermatographism (urtication after pressure) is common in urticaria.Biopsies will distinguish the type of inflammatory infiltrate.
Polymorphous light eruption (PMLE)
A hypersensitivity reaction to sun exposure that occurs often on the distal extremities. It presents with neither target lesions nor mucosal disease. Recurrence annually with the initial sun exposure is common.
Biopsy can aid in distinguishing from EM.Phototesting may elicit typical lesions.
Allergic contact dermatitis
Contact allergens can elicit an EM-like illness.Target lesions should be absent and atypical sites are likely (not extremities). [16]
Patch testing will identify offending allergens in many cases.
Molluscum contagiosum
Id reactions that are annular plaques surrounding a molluscum (pearly papules with central dells) can mimic target lesions. Careful inspection of the central zone to identify the pearly papules with a central dell will aid in diagnosis. Lesions caused by molluscum contagiosum will be both itchy and fixed for extended times, as opposed to lesions caused by EM. [18]
Unroofing the central zone of a targetoid lesion will demonstrate cheesy white material in molluscum, or fluid for blisters of EM.
Stevens-Johnson syndrome (SJS)
Severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing, with no typical target lesions. Less than10% total body surface area is affected. May present with only mucosal involvement. Drug-induction is also a clue to the diagnosis of SJS. [2] [3] [4] [16]
Biopsy shows minimal inflammation in SJS.
Toxic epidermal necrolysis (TEN)
Severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing, with no typical target lesions. Denudation of 30% or more total body surface area, drug triggers, and multiple mucous membrane involvement are typical of TEN. [2] [3] [4] [16]
Biopsy shows minimal inflammation in TEN.
SJS-TEN overlap
Severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing. No typical target lesions. About 10% to 30% total body surface area involved. [2] [3] [4]
Biopsy shows minimal inflammation.
Lyme disease
Possible antecedent tick bite, exposure in an endemic region, or erythema migrans.Usually single large expanding target lesion.
Lyme serology is positive later in disease, but may be negative early in disease.

Erythema nodosum

Weber-Christian disease
Also known as lobular panniculitis without vasculitis.Occurs predominately in women between the ages of 30 and 60.Lesions are recurrent red, swollen, tender subcutaneous nodules 1 to 2 cm in size, involving the thighs, lower legs, arms, trunk, and face.Occasionally, the lesions discharge an oily, yellow-brown liquid.Inflammation can involve lungs, intestines, pleura, myocardium, pericardium, spleen, kidney, and adrenal glands.
High sedimentation rate and leukocytosis may be the only laboratory abnormalities seen.Biopsy of the lesion shows polymorphs, lymphocytes, macrophages, and foamy histiocytes in the lobules of subcutaneous tissue. Fibroblasts replace the initial inflammatory cellular response.
Alpha-1-anti-trypsin deficiency
Can cause panniculitis.Characterised by recurrent, tender, erythaematous, subcutaneous ulcerating nodules, 1 to 5 cm wide.There is often a family history.
Serum alpha-1-anti-trypsin level is low.
Nodular vasculitis (erythema induratum or Bazin's disease)
More common in women.Presents as chronic, recurrent, erythaematous, tender nodules in the subcutaneous tissue that frequently ulcerate.Especially common in the calf area.
Can be associated with tuberculosis, giving a positive tuberculin test.A CXR may show evidence of active tuberculosis.Biopsy reveals tuberculoid granulomas with caseation and a giant cell reaction.

Essential hypertension

Drug-induced
There may be signs of acute intoxication, withdrawal, or cravings with cocaine/sympathomimetics use.History of treatment with or ingestion of non-steroidal anti-inflammatory drugs, OCPs, sympathomimetics, herbal medications (e.g., black cohosh, capsicum, ma huang), or liquorice.
Drug toxicology screen may detect an illicit substance.Hypokalaemia if excessive liquorice.
Chronic renal failure
There may be pruritus, halitosis, oedema, or change in urine output.
High serum creatinine.Chronic anaemia may be seen.Renal ultrasound may identify sclerotic or polycystic kidneys.
Aortic coarctation
Differential BP in upper and lower extremities. Absent femoral pulses.
CT, angiogram, or MRI confirms diagnosis.
Renal artery stenosis
Typically younger patients with difficult-to-control HTN.Renal artery bruits may be present.
Renal duplex ultrasound or magnetic resonance angiogram (MRA) of renal arteries confirms diagnosis.
Sleep apnoea, obstructive
Typically obese patients with daytime somnolence, snoring, or choking during sleep.
Polysomnography shows nocturnal oxygen desaturation.
Hyperaldosteronism
There may be weakness or paraesthesiae.
Unprovoked hypokalaemia.Plasma aldosterone high.Plasma renin low.Failure to suppress aldosterone with salt loading.
Hypothyroidism
Dry skin, cold intolerance, weight gain, sluggishness, and goitre.
TSH elevated in primary hypothyroidism.
Hyperthyroidism
Heat intolerance, weight loss, hyperphagia, palpitations.
TSH suppressed and levels of free thyroid hormones elevated.
Hyperparathyroidism
There are often no differentiating symptoms; however, renal colic, abdominal pain, or bone fracture may occur.
Hypercalcaemia, with elevated or inappropriately normal serum PTH.
Cushing's syndrome
Classic symptoms and signs include weight gain, moon face, dorsicocervical fat pad, abdominal striae, and easy bruisability.
Abnormal dexamethasone suppression, 24-hour urine free cortisol, and/or late-night salivary cortisol.
Phaeochromocytoma
Paroxysms of HTN, flushing, and headache.
24-hour urine screen shows elevated vanillylmandelic acid, metanephrines, and/or catecholamines.
Acromegaly
Acral (hand/foot/jaw) enlargement.
Elevated insulin-like growth factor-1 (IGF-1). Elevated serum growth hormone level, not suppressed by glucose load.
Collagen vascular disease
Signs/symptoms of systemic lupus erythematosus (SLE), rheumatoid arthritis, sclerodactly, or Hx vasculitis.
Elevated ESR, abnormal complement levels, positive anti-DNA, anti-ribonucleoprotein (anti-RNP), anti-Smith antibodies, positive rheumatoid factor.

Essential thrombocytosis

Secondary (reactive) thrombocytosis
People with secondary or reactive thrombocytosis usually have a history of infection, splenectomy, malignancy, trauma, or surgery. The thrombocytosis is usually transient and subsides when the primary stimulus ceases. Despite the high platelet count, thrombotic and/or haemorrhagic complications are uncommon.
Serum ferritin <45 picomol/L (20 nanogram/mL) suggests iron deficiency and may explain thrombocytosis.CRP >95.2 nanomol/L (>10 mg/L [>1.0 mg/dL]) and >428.6 nanomol/L (>4.5 mg/dL [>45 mg/L]) is seen in 76% and 52% of people, respectively, in reactive thrombocytosis. [15]ESR may also be raised.
Spurious thrombocytosis
Patients with mixed cryoglobulinaemia may have a temperature-dependent increase in leukocyte and platelet counts when blood samples are tested at temperatures of ≤30°C (86°F). A doubling of the platelet count may be noted.
Repeat measurements done at room temperature may be normal.
Familial essential thrombocythaemia
This is a rare disorder that is transmitted in an autosomal dominant pattern so there may be a family history.
Genetic testing for thrombopoietin and its receptor (c-Mpl) mutations can identify familial essential thrombocythaemia in patients.
Myelodysplastic syndrome (MDS)
MDS is a group of disorders characterised by clonal chromosomal abnormality, ineffective and dysplastic haematopoiesis resulting in ≥1 cytopenias, and a varying predilection to develop acute myeloid leukaemia (AML). These disorders can arise primarily without any inciting event, but may be related to previous treatment with either chemotherapy or radiation.
FBC in MDS shows normochromic or macrocytic RBCs and morphological abnormalities such as oval macrocytic RBCs and granulocytes with the pseudo-Pelger-Huet anomaly (hypogranular and hypolobulated granulocytes). Approximately 40% of patients have neutropenia and >30% have thrombocytopenia.Bone marrow histopathology in MDS demonstrates dysplasia in a proportion of undifferentiated myeloblasts.Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts; these are abnormal erythroid precursor cells that have granules around the nucleus.
Polycythaemia vera
Patients with primary polycythaemia (often called polycythaemia vera, polycythaemia rubra vera, or erythremia) may present with plethora, as excess RBCs are produced due to abnormality of the bone marrow. They may also present with thrombotic complications.
In primary polycythaemia, there may be 8 to 9 million erythrocytes/mm^3 of blood (a normal range for adults is 4-6 million), and the haematocrit may be as high as 70% to 80%. The total blood volume sometimes increases to twice as much as normal.
Primary myelofibrosis
Presenting symptoms include anaemia, bone pain, and abdominal tenderness due to splenomegaly.
Bone marrow biopsy and histopathology show replacement of marrow by collagen (fibrosis).
Chronic myeloid leukaemia (CML)
Presenting symptoms of CML and essential thrombocytosis can be exactly the same. Symptomatic patients with CML more commonly present with anaemia, easy bruising, low-grade fever, and susceptibility to infections. The most common physical examination finding in CML is splenomegaly, and the patient may complain of fullness in the left subcostal region.
Isolated thrombocytosis can be the initial clinical manifestation of CML. FBC shows that all patients with CML have elevated WBC count and half have a WBC count >100,000/microlitre. A peripheral smear shows that most WBCs are neutrophils, but basophil and eosinophil counts are also commonly raised. About 45% of CML patients present with anaemia and 15% to 30% have thrombocytosis of >600,000/microlitre.Cytogenetics testing: fluorescent in situ hybridisation analysis and real-time quantitative reverse transcription PCR (qRT-PCR) for bcr-abl gene transcripts provide the definitive diagnosis, with qRT-PCR being the most sensitive. The pathognomonic feature is the presence of a reciprocal translocation between chromosomes 9 and 22. The end product is the Philadelphia chromosome (Ph +).

Essential tremor

Parkinson's disease
Resting and action tremor, with rigidity, bradykinesia, and postural instability. Also, masked facies, cog-wheeling, gait abnormalities, and early morning dystonia. [10]
A dopaminergic agent (e.g., levodopa) trial can clarify the diagnosis.
Dystonia
Dystonic movements or postures, pain, a geste antagoniste, or muscular hypertrophy.
If the clinical diagnosis is in doubt, genetic testing can help to diagnose dystonia.
Wilson's disease
Occurs in patients <40 years of age.Characterised by resting and action tremor.Other neurological abnormalities present (e.g., dystonia, dysarthria, depression, cognitive impairment). [10]
A low serum ceruloplasmin (<200 mg/L [20 mg/dL]) would indicate that the patient had Wilson's disease. [4]Ophthalmological examination with a slit lamp reveals Kayser-Fleischer rings in most patients who have neurological signs.
Enhanced physiological tremor
All normal, healthy individuals exhibit physiological tremor.It can be enhanced by intake of stimulants and other drugs, by withdrawal from drugs or alcohol, during certain medical conditions (elevated thyroid hormone levels or low glucose level), and by stress and fatigue. [4]Enhanced physiological tremor occurs in the absence of a neurological disease and is high-frequency postural and kinetic tremor that occurs in the arms, legs, and voice but not the head.
A medicine history looking for agents that cause enhanced physiological tremor, and TFTs screening for hyperthyroidism.In some patients, quantitative computerised tremor analysis with accelerometers attached to the arms can help in diagnosing enhanced physiological tremor. [38]It is usually reversible once the cause is corrected.
Drug-induced tremor
Occurs following ingestion of certain drugs (e.g., lithium carbonate, theophylline valproic acid, ciclosporin [cyclosporine], caffeine).The tremor may affect the hands, arms, head, eyelids, or other muscles, but rarely affect the legs or feet.The shaking usually involves small, rapid movements, >5 times a second.
The tremor will occur in a reasonable time frame following drug ingestion.

Eustachian tube dysfunction

Sensori-neural hearing loss
There may be no differences in signs and symptoms.
Positive Rinne's test: air conduction of a note from a tuning fork is better than nerve conduction, as they are both depreciated.

Ewing Sarcoma

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Extrapulmonary tuberculosis

Lymphoma
There may be no difference in signs and symptoms.Constitutional symptoms and widespread lymphadenitis are more common in lymphoma.TB lymphadenitis is most commonly found in the cervical or supraclavicular regions.
Chest x-ray may show abnormalities consistent with prior pulmonary TB in about 25% of patients with TB lymphadenitis.FNA will usually be able to diagnose TB lymphadenitis; if this is non-diagnostic, excisional biopsy must be performed.
Non-tuberculous mycobacteria lymphadenitis
There may be no difference in signs and symptoms.TB lymphadenitis predominates in patients older than 12 years and non-tuberculous mycobacteria (NTM) is more common in children younger than 12 years of age.TB lymphadenitis predominates in women of Asian background from TB-endemic areas. [1]
Chest x-ray may show abnormalities consistent with prior pulmonary TB in about 25% of patients with TB lymphadenitis.In an adult with acid-fast bacilli (AFB) or caseating granulomas on FNA, empiric therapy for TB can be started. This is also true if a child has epidemiological risk factors for TB, pending results of culture.In a child with presumed NTM, the diagnosis must be proved with culture results. [20] [67]
Sarcoidosis
Features of sarcodiosis, such as intrathoracic lymphadenopathy and arthralgias, may be present. A careful review of epidemiological risk factors for TB can be performed.
Tuberculin skin testing (TST) will usually be negative with sarcoidosis and chest x-ray may have findings more consistent with TB or sarcoidosis.Granulomas are non-caseating in sarcoidosis, although it is not diagnostic.AFB may be seen on FNA in TB lymphadenitis. Culture for AFB is negative in sarcoidosis.
Malignant pleural effusion
There may be no difference in signs and symptoms.
TST may be negative in up to 40% of patients with pleural TB.CT scan of the chest may show findings more consistent with malignancy (particularly if primary bronchogenic) or with pulmonary TB. A search for a primary in metastatic disease may also diagnose the aetiology (e.g., in an effusion due to metastatic breast or ovarian cancer). Cytological evaluation of the pleural effusion may diagnose a malignant effusion.Pleural biopsy may reveal granulomas, AFB, or malignant pathology.Video-assisted thoracic surgery (VATS) differentiates between an effusion-caused TB and those caused by malignancy.
Cryptococcal meningitis, other fungal CNS infections, neurosyphilis
The differential diagnosis of TB meningitis includes disease processes that cause a subacute to chronic meningitis and a lymphocyte-predominant pleocytosis.Cranial nerve abnormalities are more common in TB.
CSF analysis is the key to making the diagnosis.AFB and fungal stain and cultures are usually diagnostic.Nucleic acid amplification test (NAAT) of CSF may also help in diagnosis.An elevated adenosine deaminase (ADA) may support the diagnosis of TB. [68]TST has poor sensitivity with CNS TB (approximately 50%). [43]
Inflammatory bowel disease
There may be no difference in signs and symptoms.The presence of epidemiological risk factors for TB, a positive TST, or chest x-ray findings consistent with TB all support TB as the aetiology.The presence of ascites is more consistent with a diagnosis of TB enteritis.
Colonoscopy with biopsy is the best method for diagnosis, with a sensitivity of up to 80%.The presence of mesenteric lymphadenopathy with central necrosis is suggestive of TB. [59]
Peritoneal carcinomatosis
Epidemiological risk factors may be present in patients with TB.
Cytological analysis of ascites identifies patients with malignant ascites.CT scan may identify a primary neoplasm.
Spontaneous bacterial peritonitis (SBP)
In patients with a history of cirrhosis and epidemiological risk factors for TB, a high index of suspicion must be maintained for TB peritonitis.Symptoms are more chronic in those with TB enteritis.
Patients with TB peritonitis usually have ascites with a low serum-ascitic albumin gradient (SAAG) and lymphocytes >30%. However, cirrhotics may have peritoneal TB with a low protein and PMNs >250/mL, mimicking SBP.In TB peritonitis, CT scan may reveal abdominal lymphadenopathy.Differentiating tests include NAAT, ADA, AFB culture, and peritoneal biopsy.
Fever of unknown origin (FUO)
There may be no difference in signs and symptoms.The presence of epidemiological risk factors for TB or coexistence of pulmonary TB may help diagnosis.
EPTB, especially disseminated disease, may be responsible for FUO. TST will usually be negative. Diagnosis may require transbronchial, liver, or bone marrow biopsies.

Factitious disorders

Malingering
External incentives are present, such as desired medications (stimulants, opiates), disability payments, and leaving incarceration for a more desirable setting.In factitious disorder, patients are motivated by a desire to assume the sick role rather than by the hope to achieve external rewards.
No differentiating tests. Diagnosis based on history.
Somatoform disorders
Symptoms are produced unconsciously in somatoform disorders, whereas in factitious disorder the signs or symptoms of illness are intentionally feigned. It may be difficult to differentiate, given that the patient is unlikely to initially disclose his or her motivation.
No differentiating tests. Diagnosis based on history.
Organic disease
When diagnostic testing does not determine a cause for signs or symptoms, the patient may have an actual rare or difficult-to-diagnose illness. It may be difficult to differentiate, given that the patient with factitious disorder is unlikely to initially disclose his or her motivation.
No differentiating tests. Diagnosis based on history.

Faecal incontinence in adults

Colorectal cancer
Bleeding, altered bowel habit, tenesmus, sudden onset of symptoms, family history of bowel cancer, previous polyps.
Colonoscopy: reveals mass within the colon.Barium enema: typical apple core stricture appearance as passage of barium is restricted by the mass.
Cauda equina syndrome
Lower back pain, weakness and numbness in lower limbs, sciatic pain radiating down one or both legs, perianal anaesthesia.
MRI spine: may show degenerative arthritic changes, disc herniation, infection, or tumours causing spinal cord compression.
Crohn's Disease
Inflammatory bowel disease may alter bowel habit due to inflammation and altered bowel compliance. The resulting rapid transit may overcome the continent mechanisms. Often blood is present in the stools. There may be abdominal pain and constitutional symptoms.
Barium enema or barium meal: may show strictures, ulceration, and sometimes fistulae.Colonoscopy: good visualisation of small ulcers, allows biopsies to be taken.Capsule endoscopy: lesions in the small bowel.
Ulcerative colitis
Inflammatory bowel disease may alter bowel habit due to inflammation and altered bowel compliance. The resulting rapid transit may overcome the continent mechanisms. Often blood is present in the stools. There may be abdominal pain and constitutional symptoms.
Flexible sigmoidoscopy or colonoscopy: erythematous mucosa, ulceration, friable mucosa.Rectal biopsy: cryptitis, crypt branching, plasma cells in the lamina propria, crypt abscesses.Small bowel follow-through: strictures, absence of lesions in small bowel.
Traveller's diarrhoea
Usually occurs within 2 weeks of arrival in a developing world country, often accompanied by nausea and vomiting, tenesmus, and abdominal cramping.
Faecal leukocytes: presence of large numbers of white blood cells.Stool culture: growth and identification of bacterial aetiology.Stool ova and parasite examination: identifies common parasites.Giardia stool antigen test: positive if Giardia present.
Acute diarrhoea
Unusual food intake in last 2 to 3 days, other family members may be affected, recent travel, accompanied by vomiting, and often abdominal cramps. Recent hospitalization or use of broad-spectrum antibiotics may suggest Clostridium difficile infection.
Stool culture: positive for growth if infectious cause.Stool test for Clostridium difficile toxin.
Chronic diarrhoea
Greater than 3 loose stools/day for >4 weeks; may be associated with weight loss, blood in stool, abdominal pain, or bloating. Can be caused by a variety of aetiologies including coeliac disease, diverticular disease, and lactose intolerance.
Duodenal biopsy: increased intraepithelial lymphocytes, villous atrophy, and crypt hyperplasia (coeliac disease).Colonoscopy: diverticular present (diverticular disease).Lactose tolerance test: blood sugar does not increase after drinking a liquid containing lactose (lactose intolerance).
Fistulae
History of anorectal abscess or inflammatory bowel disease; fistulae opening may be seen around anus or on proctoscopy.
Examination under anaesthetic: visualisation and examination of fistula tract.

Faecal incontinence in children

Non-specific toddler's diarrhoea
Age of patient is limited to early childhood, first 2 years of life
None. Stool studies or other laboratory studies are normal.
Irritable bowel syndrome with alternating constipation and diarrhoea
Hx of alternating constipation and diarrhoea associated with pain and abdominal discomfort.Abdominal bloating or distension that increases during the day and is not associated with nausea and vomiting.No significant findings following abdominal examination.
FBC normal; presence of anaemia suggests non-IBS disease.Stool studies normal; presence of WBCs or parasites in stool suggests non-IBS disease.Plain abdominal x-ray, flexible sigmoidoscopy, and colonoscopy all normal.
Infectious diarrhoea
Usually accompanied by fever, vomiting, and bloody stools.
Stool studies may be positive for RBCs and WBCs.Faecal culture may grow bacteria.Ova and parasites may be seen on microscopic examination of stool.

Failure to thrive

Small but healthy
By definition, 5% of children will track below the 5th percentile on growth charts. A consistent trajectory suggests they are small, but healthy. Indicators of whether the child is small but healthy or experiencing FTT include: examination of growth and past medical history, feeding behaviour, development, and response to feeding recommendations.
None needed.
Small for gestational age
Infants with compromised in utero growth (small for gestational age) often have poor postnatal growth.
None needed.
Prematurity
Infants with prematurity often have poor postnatal growth. Gestational age needs to be factored into interpretation of growth.
Plotted on appropriate growth chart.

Familial adenomatous polyposis syndromes

MutYH polyposis
Cannot be definitively distinguished by any key characteristics in the personal history or physical examination. However, if the patient is from a FAP kindred with a known adenomatous polyposis coli (APC) mutation, then this diagnosis is very unlikely.
Germline DNA testing for bi-allelic MutYH mutations. [24] [25]
Juvenile polyposis
Family history of juvenile polyposis. Patients may present with iron deficiency anaemia, obstructive symptoms, or evidence of a gross GI bleed. A subset may have clubbing of fingernails and telangiectasias.
Juvenile polyps in the stomach, small bowel, and/or colon. Polyps are juvenile retention polyps with mucin. Germline testing for SMAD4, BMPR1A, and PTEN gene mutations may be positive. Patients with SMAD4 mutations may also have hereditary haemorrhagic telangiectasias.
Peutz-Jeghers syndrome
Clinical presentation may be similar. Hyper-pigmentation of the buccal mucosa and lips are commonly seen. Small bowel intussusceptions and/or obstruction is a common presentation.
Polyp histology shows hamartomatous lesions. STK11 genetic testing may be positive.
Mixed adenomatous hyperplastic polyposis
Clinically asymptomatic.
Colonoscopy shows both flat and pedunculated polyps, with flat polyps >1 cm in diameter in the right side of the colon. Histology reveals both hyperplastic and adenomatous polyps; the right-sided polyps may also have sessile serrated adenomatous features histologically.
Hyperplastic polyposis syndrome
Clinically asymptomatic.
Colonoscopy shows flat polyps, particularly in the right side of the colon, >1 cm in diameter. It is important to distinguish these polyps from the hyperplastic polyps of <6 mm diameter in the left side of the colon and in the rectum, which occur without larger right-sided hyperplastic polyps and which have no known malignant risk.
Colonic lymphoid hyperplasia
Can cause abdominal pain, haematochezia, chronic diarrhoea, recurrent intussusceptions in children.
Endoscopically, multiple polypoid lesions may be present throughout the colon or in a segment of the colon. Pathology reveals lymphoid hyperplasia, not adenomatous tissue.

Familial Mediterranean fever

Acute sarcoidosis
Cough; dyspnoea; chronic fatigue; wheezing; rhonchi; lymphadenopathy; photophobia; red, painful eye; erythema nodosum.
FBC: anaemia, leukopenia. Serum calcium: elevated. Angiotensin-converting enzyme level: elevated.Chest x-ray: hilar and/or paratracheal adenopathy with upper lobe predominant, bilateral infiltrates; pleural effusions (rare) and eggshell calcifications (very rare) may be seen.
Rheumatoid arthritis
Age 50 to 55 years; more likely in females; active systemic arthritis lasting >6 weeks; most commonly affects bilateral metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsalphalangeal (MTP) joints; rheumatoid nodules.
Rheumatoid factor: positive. Anticyclic citrullinated peptide antibody: positive.Joint x-ray: typical pattern of erosions.
Vasculitis
Upper extremity and jaw claudication; headache and scalp tenderness; haematuria; asymmetrical brachial pulses; bruits; foot drop, wrist drop; cutaneous ulcers; palpable purpura.
ESR: >100 mm/hour. CRP: elevated. ANCA (anti-neutrophil cytoplasmic antibody): positive.Urinalysis: haematuria, proteinuria, red blood cell casts.Biopsy of affected tissue: vessel wall necrosis, fibrinoid necrosis, karyorrhexis, and red blood cell extravasation.
Seronegative spondyloarthropathy
Back pain; iritis; enthesitis.
HLA B27: positive.Joint x-ray: erosions. Ultrasound: enthesitis. MRI: bone marrow oedema.
Acute appendicitis
May be clinically indistinguishable.Anorexia; RLQ tenderness, guarding, and rebound tenderness.
Abdominal CT and ultrasound: abnormal appendix (diameter >6 mm).
Acute abdomen
May be clinically indistinguishable.Involuntary guarding, reduced bowel sounds.
Abdominal x-ray and CT: evidence of a different underlying cause.
Hyperimmunoglobulinaemia D syndrome (HIDS)
Dutch and other European ancestry. Autosomal recessive.Disease onset is typically in infancy. Attacks typically last 3 to 7 days and become less frequent and severe with age.Severe pain with vomiting and constipation; symmetric arthritis; lymphadenopathy very common; splenomegaly occurs in almost half of children; cutaneous vasculitis is common; aphthous ulcers.
Targeted genetic analysis will show mutation in the MVK gene, which regulates the function of the protein mevalonate kinase. [29] [43] [44] [45] [46]Serum IgD may be elevated. However, this is not specific or sensitive and could be elevated in other auto-inflammatory syndromes, other chronic inflammatory conditions, and in children with mevalonate kinase deficiency (nearly half of whom will have persistently normal serum IgD levels). [45] [46]
TNF receptor-associated periodic syndrome (TRAPS)
The term TRAPS was coined in 1999 with the discovery that the disease-causing genes were identified on chromosome 12. [47] It is also known as familial Hibernian fever. [48]Any ethnicity but mostly northern European. Autosomal dominant or sporadic.Attacks typically last days to weeks and include migratory macules, patches, papules, and plaques; migratory myalgia; periorbital oedema; pleurisy; conjunctivitis; scrotal pain. Amyloidosis occurs in 10%.
Targeted genetic analysis will show mutations in the TNFRSF1A gene, which regulates the protein TNFRSF1A. [29] [43] [44] [45] [46]Serum levels of soluble TNF receptor are reduced. [45] However, this is not sensitive or specific, has high variability of results, and is only available in specialised and research laboratories.The associated immunophenotype of cutaneous lesions is characterised by an infiltrate of CD68+ (monocytes), CD3+, CD4+, and CD8+ cells (T cells).Immunofluorescence studies of lesional skin reveal IgM and C3 at the dermal-epidermal junction; diffuse IgA, IgG, and C3 deposition; and fibrinogen in the upper dermis. [46]
Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA)
One of the cryopyrinopathies.Any ethnicity. Autosomal dominant.Generalised urticaria-like eruptions and neutrophilic eccrine hidradenitis; mental retardation; destructive arthritis; anterior uveitis, optic disc changes and blindness; perceptive deafness.
Targeted genetic analysis will show mutations in the CIAS1 that affect the function of the protein cryopyrin. [43] [44] [46]
Familial cold auto-inflammatory syndrome (FCAS)
Also known as familial cold urticaria. One of the cryopyrinopathies.Northern European ethnicity. Autosomal-dominant inheritance.Onset in early infancy and sometimes 2 hours after birth. Cold or generalised cooling after sweating can trigger an attack. Urticarial itchy, burning rash and arthritis during attacks. Rash starts on extremities then becomes generalised. Profuse sweating during attacks. Conjunctivitis and myalgias. Attack duration <24 hours.
Targeted genetic analysis will show mutation in the CIAS1 gene, which affects the function of cryopyrin. [43] [44] [45] [46]Sharp rise in serum interleukin (IL)-6 during attacks. [45] However, this is not sensitive or specific, has a high variability of results, and is only available in specialised and research laboratories.
Muckle-Wells syndrome (MWS)
One of the cryopyrinopathies. Autosomal dominant inheritance.Similar features to FCAS but more frequent attacks, from several times per week to monthly and slightly longer duration. Distinguished from FCAS by the development of perceptive deafness and systemic amyloidosis (25%), which is rare in FCAS.
Targeted genetic analysis will show mutation in the CIAS1 gene, which affects the function of cryopyrin. [43] [44] [45] [46]Sharp rise in serum IL-6 during attacks. [45] However, this is not sensitive or specific, has a high variability of results, and is only available in specialised and research laboratories.
Syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA)
Autosomal dominant.Scarring cystic acne; pyoderma gangrenosum; pyogenic sterile non-axial arthritis.
Targeted genetic analysis will show mutations in the CD2BP1, which regulates the function of the protein CD2-binding protein 1. [43] [44] [46]It has also been shown that TNF-alpha levels are elevated in the mononuclear cells of these patients. [49] However, this is not specific or sensitive.

Febrile neutropenia

Drug fever
Drug fevers are typically high fevers that are often cyclical in nature.Drug fevers may be associated with an eosinophilia, acute interstitial nephritis, or drug-induced hepatitis.They should improve with discontinuation of the offending agent.
FBC: eosinophilia.Culture: negative.
Tumour fever
Progression of the underlying malignancy can be associated with tissue necrosis and inflammation that can yield low-grade or high fevers that do not improve with antibiotics. However, patients with haematological malignancies often present with diurnal fevers.
There are no specific laboratory tests to indicate a tumour fever.Cultures: negative.Imaging may demonstrate progression of disease. This is usually a diagnosis of exclusion when fevers persist, despite negative cultures and broad antibiotic coverage.
Thromboembolism
Malignancy is a risk factor for thrombosis, which can cause fever, especially in the setting of compromised blood flow to tissue with associated necrosis.Signs or symptoms of a deep vein thrombosis with extremity pain, erythema, or swelling may be present.Additionally, signs or symptoms of a pulmonary embolism may be present with shortness of breath, tachycardia, chest pain, hypoxaemia, and cerebral embolism with new neurological signs or symptoms.
Doppler ultrasounds, CT angiograms of the chest and/or brain, and echocardiograms (either trans-thoracic or trans-oesophageal) will reveal the presence of a thrombus or thromboembolic disease.
Paraneoplastic syndromes
Many malignancies are associated with the development of paraneoplastic syndromes, which are characterised by the development of auto-antibodies, presumed to have developed in response to tumour antigens. The resultant syndromes can mimic the known autoimmune syndromes. In addition, there are a number of paraneoplastic syndromes that affect the nervous system and are well characterised and associated with particular underlying malignancies.
There is a paraneoplastic syndrome antibody panel that can be sent to from the peripheral blood and/or the cerebral spinal fluid. If positive, these are helpful as they are specific. They are not sensitive, however, and their absence does not rule out a paraneoplastic syndrome.

Febrile seizure

Acute bacterial meningitis
Persistent irritability and lethargy, prolonged postictal obtunded consciousness, skin rash, bulging fontanelle, and nuchal rigidity.
Typical CSF abnormalities are pleocytosis, elevated protein, low glucose level, and positive culture.
Viral meningitis
Fever, headache, neck stiffness are common. Nausea, vomiting, and photophobia can also occur.
CSF: lymphocytic pleocytosis.Glucose is normal or high.Gram stain and bacterial culture are negative; viral culture and PCR may be positive.
Viral encephalitis
Prodromal upper respiratory symptoms with fever and malaise, followed by headache, stiff neck, and seizure.Skin rash also common.
LP may show pleocytosis and increased protein but is sometimes normal.Culture is negative for bacteria.Results of viral studies are positive (i.e., herpes simplex, varicella).
Acute encephalopathy
Viral prodrome, vomiting, followed by profound impairment of consciousness and seizures.Toxins include aspirin (Reye's syndrome).
LP may reveal elevated CSF pressure, increased cell count, and protein, with moderately decreased glucose.Bacterial cultures are negative.An elevated CSF/serum albumin ratio indicates an impaired blood-brain barrier and is the earliest sign of acute viral encephalopathy. [45]Liver enzymes and blood ammonia are elevated.Low blood glucose may be present.EEG abnormalities are variable but are of prognostic significance.MRI abnormalities may include bilateral thalamic necrosis, white matter lesions, and brain oedema. MRI may also be normal.Viral studies may be positive (e.g., influenza A).
Epileptic seizure
Afebrile seizure.
EEG shows paroxysmal epileptiform discharges (e.g., spikes, spike and slow wave).
Generalised epilepsy with febrile seizures plus (GEFS+)
Childhood onset of multiple febrile seizures persisting beyond 5 years and associated with afebrile seizures.Seizures cease by mid-childhood (median age 11 years).An evolving composite of many syndromes, with shared genetic susceptibility. [46]
Genetic tests show links to chromosomes 2q24, 19q13 and 5q31, an autosomal-dominant inheritance with 50% penetrance.SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for GEFS+. [24]
Hot water epilepsy (HWE)
The diagnosis is made by history.Seizures are usually complex partial and are precipitated by bathing or pouring hot water (40-50°C [104-122°F]) over the head.Most common in India and Turkey.Not age-dependent, but males predominate 3:1. Only 7% have history of febrile seizures.Family history positive for epilepsy in 22%, and for HWE in 7%. [47]
Interictal EEG shows temporal spikes.
Breath-holding spells
Afebrile infant, with an apnoeic attack, cyanosis, LOC, and short generalised episodes of jerking of extremities after a crying spell.The breath is held in expiration.Onset is 6 to 18 months of age, similar to that of febrile seizures.Some non-cyanotic, pallid breath-holding spells result from vagal stimulation after an unpleasant, unexpected stimulus.These are associated with cardiac asystole and are accompanied by syncope or anoxic seizure.
EEG is usually normal and the attacks do not predispose to epilepsy. [48]FBC and serum ferritin may uncover an associated iron deficiency anaemia, reported in 20% to 69% cases.Iron supplements are effective in prevention. [49]
Dravet's syndrome: severe myoclonic epilepsy of infancy (SMEI)
Intractable epilepsy, resembling febrile seizure disorder in first year.Seizure onset early, recurrent (>5), prolonged, often focal and clonic.
SCN1A mutation analysis positive. [50]

Felty's syndrome

Large granular lymphocyte (LGL) syndrome
A low-grade malignancy associated with neutropenia and splenomegaly, and 25% of patients have rheumatoid arthritis (RA). FS and RA are now considered to form an overlap syndrome. [15]Arthritis in LGL syndrome tends to be less aggressive than in FS, with fewer extra-articular RA manifestations. [8]LGL is more likely if onset of arthritis and neutropenia is simultaneous.
RF may be negative.Peripheral blood smear and bone marrow examination show an expanded lymphocyte population with typical LGLs.Immunophenotyping shows an expanded population of lymphocytes expressing CD2, 3, 8, 16, and 57.T-cell receptor gene rearrangement studies show clonal cytogenetic abnormalities.
Lymphoproliferative disorders
Typical features of RA may not be present on examination.There may be widespread lymphadenopathy with hepatosplenomegaly.Hx may reveal presence of B-cell symptoms (e.g., night sweats, fever, weight loss).
RF may be negative.Peripheral blood smear and bone marrow examination may show infiltration by lymphoma cells.Lymph node excision biopsy may be necessary to characterise the type of lymphoma.
Myeloproliferative disorders
Typical features of RA may be absent on examination.
FBC may show anaemia, neutropenia, lymphocytosis, thrombocytopenia, or thrombophilia.Peripheral blood smear and bone marrow examination may show infiltration with abnormal cells, which can be characterised by cytogenetic analysis.
Systemic lupus erythematosus
Absence of typical articular and extra-articular features of RA such as erosive arthritis or rheumatoid nodules.Other features that may suggest SLE include typical skin rashes such as a malar rash, photosensitivity, or discoid lupus, and presence of nephritis or central nervous system involvement.
Lymphopenia is more common in SLE.Hand x-rays are unlikely to show erosive changes.High-titre ANA and double-stranded (ds) DNA suggest SLE.Urinalysis may show proteinuria and haematuria suggestive of SLE nephritis.
Anti-TNF-induced lupus
Patients with RA treated with anti-TNF agents may develop anti-TNF-induced lupus (ATIL), characterised by increased ANA positivity, development of dsDNA antibodies, and clinical features of drug-induced lupus such as fever, malaise, myalgia, and rash.Symptoms usually resolve on withdrawal of anti-TNF agent. [13]Splenomegaly is not usually a feature of ATIL. [13]
Increased titre of ANA, development of dsDNA antibodies, which are usually IgM dsDNA.
HIV infection
Typical features of RA may be absent.Systemic symptoms, such as fevers or constitutional upset, may be common.There may be risk factors for development of HIV infection.
RF may be negative.Virological testing confirms HIV infection.
CMV infection
Typical features of RA may be absent.Systemic symptoms such as fevers or constitutional upset may be common.
Inflammatory markers CRP and ESR may not be elevated in viral infection.RF may be negative.Virological testing confirms CMV infection.
Sarcoidosis
Patients may have arthritis, typically involving ankles, knees, and hands, but it is rarely deforming or erosive.Patients may also have uveitis, lymphadenopathy, parotid gland enlargement, enthesitis, skin involvement with erythema nodosum, or lupus pernio.
CXR may reveal bilateral hilar lymphadenopathy.Serum angiotensin-converting enzyme may be raised.Hand x-rays are unlikely to show RA changes and erosions.Biopsy of lymph nodes, affected organs, or bone marrow may show non-caseating granulomas.
Amyloidosis
Patients with long-standing RA are at risk of developing amyloidosis.Non-specific symptoms such as weight loss and fatigue, together with peripheral oedema due to cardiac or renal involvement, may be present, as well as paraesthesias suggesting peripheral neuropathy.Examination may show cardiac failure.
Urinalysis may show proteinuria.Blood tests may show renal impairment.CXR may show heart failure.Ultrasound or CT scan abdomen may show hepatosplenomegaly.Serum amyloid P component scintigraphy may confirm diagnosis.Biopsy of rectum or affected organ stained with Congo red shows presence of amyloid.
Liver cirrhosis
Hx of alcohol excess or chronic viral hepatitis infection that may suggest liver cirrhosis.Typical features of RA may be absent on examination.Typical features of chronic liver disease such as spider nevi, gynaecomastia, ascites, or jaundice may be present.
RF may be negativeLFTs may be abnormal.Abdominal ultrasound may show features of cirrhosis and ascites.

Female sexual dysfunction

Sexual aversion
The thought of sexual activity as well as any sexual experience is highly distressing and the person reacts with phobic anxiety.
There is no test available to differentiate sexual aversion from sexual desire/interest disorder. Rather, a careful clinical assessment confirming phobic-like anxiety and extreme avoidance of any sexual stimuli would be characteristic of sexual aversion and not of sexual desire/interest disorder.
Marital discord
Lack of response and desire is logical and normal when there is insufficient emotional closeness.Response alone or to erotica is normal unless depression is comorbid.
Marital discord can be the main aetiology of a woman's sexual dysfunction. Only after addressing the discord can any remaining sexual dysfunction be confirmed.Self-report questionnaires (e.g., the Dyadic Adjustment Scale) may provide a cursory overview of the degree of marital dissatisfaction.

Fetal alcohol spectrum disorders

Fetal hydantoin syndrome
Maternal history of phenytoin use during pregnancy.Depressed nasal bridge, and short nose with bowed upper lip. [33] [49]
There are no differentiating tests; diagnosis is based on history and examination.
Fetal valproate syndrome
Maternal history of valproate use during pregnancy.High forehead, infraorbital crease or groove, small mouth, and a narrow bifrontal diameter. [33] [49]
There are no differentiating tests; diagnosis is based on history and examination.
Toluene embryopathy
Maternal history of toluene exposure during pregnancy.Large anterior fontanelle, downturned corners of the mouth, hair patterning abnormalities, and ear abnormalities. [17] [33]
There are no differentiating tests; diagnosis is based on history and examination.
Williams syndrome
Wide mouth with full lips, stellate pattern of the iris, a loquacious (talkative) personality, and musculoskeletal and cardiac problems. [33] [49] [50]
Deletion of one copy of the elastin gene in the 7q11.23 region of chromosome 7 seen on fluorescent in-situ hybridisation.Elevated serum calcium levels (hypercalcaemia).Supravalvular aortic stenosis, pulmonary stenosis, or peripheral pulmonary stenosis on echocardiogram.
Brachmann-de Lange syndrome
A single bushy eyebrow (synophrys), long eye lashes, downturned mouth, high arched palate, and short limbs. [33] [49]
Genetic analysis may show mutations in the NIPBL and SMC1A genes.
Maternal phenylketonuria
Small, upturned nose, round face, and a prominent glabella. [33] [49]
Elevated maternal phenylalanine levels.Genetic analysis detects one of numerous mutations that have been found in the gene that encodes for phenylalanine hydroxylase on chromosome 12 in the region q22-24.1.

Fibrocystic breasts

Chest wall pain
Pain of chest wall origin is constant and non-cyclical.May be related to physical activity.On examination, the pain is elicited upon palpation of the chest wall by carefully displacing the breast tissue.
Clinical differentiation usually suffices.
Costochondritis
Pain over the anteromedial aspect of the chest wall, over the costochondral cartilaginous junction.
Clinical differentiation usually suffices.
Fibroadenoma
More often occurs in younger women who have a well-circumscribed palpable breast mass.
Biopsy of breast mass reveals fibroadenoma.
Breast cancer
May present with a palpable mass, often firm to palpation.Presence of skin retraction or fixation to the chest wall should raise the suspicion of breast cancer.
Biopsy of breast mass reveals breast cancer and type.
Intracystic papilloma
May be able to feel small lump under nipple on examination.
Breast biopsy is required for a definitive diagnosis and to rule out cancer.Ultrasound, ductogram, and cytological examination of discharge for malignant cells are also useful.

Fibromyalgia

Myofascial pain syndrome (MPS)
Myalgia is localised, typically to an extremity and the attached truncal musculature.In contrast to the tender points of fibromyalgia, trigger points are the hallmark of MPS, with pressure over these areas not only reported as tender but causing radiation and reproduction of the pain.Some experts consider MPS to be a localised form of fibromyalgia.
Patients with localised MPS do not have evidence of widespread central sensitisation.
Vitamin D deficiency
Low vitamin D levels are associated with widespread body pain. [21] [22] It is very difficult to differentiate from fibromyalgia.
Serum 25-hydroxyvitamin D level is low.
Chronic fatigue syndrome (CFS)
There is considerable overlap between fibromyalgia and CFS, with most patients with fibromyalgia meeting criteria for CFS, and most CFS patients reporting widespread body pain. [23]
No differentiating tests.
Rheumatoid arthritis (RA)
As with other rheumatological conditions, fibromyalgia may co-exist with RA, making the diagnosis challenging.Patients with RA will have not only widespread body pain and arthralgias, but should also have signs of active synovitis on physical examination.If a patient with RA also has positive tender points, fibromyalgia is likely. If the patient is treated for RA with subsequent resolution of synovitis and markers of inflammation, yet the patient still has widespread pain and fatigue, the most likely cause is fibromyalgia.
RF factor is usually positive.Markers of systemic inflammation (ESR, CRP) are typically elevated.
Systemic lupus erythematosus (SLE)
SLE and fibromyalgia may co-exist.
Strict criteria for the diagnosis of SLE must be met; an isolated positive ANA test is not enough to establish the diagnosis of SLE in a patient with widespread pain as ANA is positive in up to 10% of the general population.
Osteoarthritis
Joint swelling and inflammation are common in osteoarthritis, but not in fibromyalgia unless it is a concomitant diagnosis.
X-rays are characteristic: joint space narrowing, subchondral sclerosis, osteophytes, subchondral cysts.
Ankylosing spondylitis
Patients have limited range of movement of the spine; spine movement in fibromyalgia is typically maintained.
X-ray features are characteristic: erosions and osteitis at the ischial tuberosities, iliac crest, symphysis pubis, and femoral trochanter.
Polymyalgia rheumatica (PMR)
Patients are typically older (>55 years of age) on presentation than those with fibromyalgia.PMR is associated not only with hip and shoulder girdle pain, but also with significant weakness and stiffness, in contrast to fibromyalgia, where weakness, if present, is usually only of a mild degree due to deconditioning.PMR typically responds extremely well to corticosteroids, whereas patients with fibromyalgia will not improve with corticosteroid treatment.
ESR, CRP, or other markers of inflammation are usually elevated.
Hypothyroidism
Patients with hypothyroidism may have muscular aching and prominent fatigue that improves on replacement of thyroid hormone.A routine TSH test is recommended for patients presenting with suspicion of fibromyalgia. Fibromyalgia and hypothyroidism may co-exist.
TSH is elevated and free T4 is low.
Myositis (dermatomyositis and other inflammatory myopathies)
Weakness and muscle fatigue are present (and more common than pain) in patients with a primary muscle inflammatory condition.
CK or aldolase levels are elevated.
Chronic liver disease
Patients with liver disease, most notably hepatitis C, often have myalgias.
Elevated LFTs; presence of hepatitis C antibody.
Iron deficiency anaemia
Patients with myalgias and iron deficiency often report improvement in symptoms with iron replacement.
Low serum iron levels, low transferrin saturation.

Focal segmental glomerulosclerosis

Membranous nephropathy
There are no distinguishing clinical features.
Light microscopy of renal biopsy specimen reveals thickened capillary walls with patent capillary lumina. Subepithelial deposits are seen and trichrome stain reveals spikes. Immunofluorescence microscopy reveals positive granular capillary wall staining for IgG, with C3 and both kappa and lambda light chains.
Minimal change disease
Responsible for most cases of nephrotic syndrome in children.Almost always associated with nephrotic syndrome at the onset of disease.
Electron microscopy of renal biopsy specimen shows diffuse podocyte effacement. Light and immunofluorescence microscopy are normal.
Amyloidosis
Orthostatic hypotension and peripheral neuropathy often present.Can affect the heart, causing jugular venous distension and breathlessness.Periorbital purpura with eyelid petechiae is a specific sign.
Serum or urine electrophoresis reveals monoclonal protein.Light microscopy of renal biopsy specimen reveals glomerular amyloid deposits with positive Congo red staining under polarised light. Electron microscopy reveals deposition of protein fibrils.
Diabetic nephropathy
Hx of diabetes is present.Other features of diabetic tissue disease may be noted such as diabetic retinopathy on ophthalmoscopy.
Renal biopsy reveals classic Kimmelstiel lesions (nodular glomerular intercapillary lesions) in 10% to 50% of cases. Arteriolar lesions with hyaline material involving both afferent and efferent vessels are prominent.
Membranoproliferative glomerulonephritis
Associated with autoimmune diseases (SLE, Sjogren's), hepatitis C, endocarditis. May present with nephrotic syndrome. Glomerular haematuria may also be present. Complement levels may be low; cryoglobulins may be present.
Light microscopy of renal biopsy specimen reveals a range of glomerular appearances from hypercellularity to sclerosis and mesangial expansion. Double contouring of the basement membrane ('tram-track' appearance) can be seen with silver stain. Dense deposits are seen in some types of the disease.
Light chain deposition disease
Liver and cardiac involvement in 25% of patients.Renal failure is rapid.
Light microscopy of renal biopsy specimen shows nodular glomerulopathy with distortion of the glomerular architecture by deposition of amorphous, eosinophilic material.Immunofluorescence microscopy reveals monotypic light chains in the glomeruli.Electron microscopy reveals subendothelial deposits in the glomerulus and outer aspect of tubular basement membrane.

Folate deficiency

Cobalamin (B12) deficiency
May be associated with neurological and neuropsychiatric manifestations: specifically, decreased vibration sense, peripheral neuropathy, gait abnormalities, dementia, depression, and visual impairment.Clinical and haematological response to treatment confirms diagnosis.
Serum vitamin B12 levels are low.Both homocysteine and methylmalonic acid are elevated.
Thiamine-responsive megaloblastic anaemia
Diabetes mellitus and sensorineural deafness are present, in addition to megaloblastic anaemia.Megaloblastic anaemia and diabetes mellitus respond partially to thiamine therapy.
Ringed sideroblasts are seen in the bone marrow.Serum folate level is normal.
Hereditary orotic aciduria
Growth retardation, neurological abnormalities, and obstructive uropathy are associated with hypochromic megaloblastic anaemia, with or without congenital malformations and immune deficiency.Replacement of uridine corrects anaemia, reduces orotic crystalluria, and improves other sequelae.
Orotic acid crystalluria is present.Serum folate level is normal.
Alcoholic liver disease
Nutritional deficiencies and macrocytic anaemia may be the presenting features. History reveals alcohol abuse.
Elevated liver enzymes.Liver biopsy shows fatty liver, inflammation, and/or cirrhosis.
Hypothyroidism
Constipation, weight gain, cold intolerance, hoarse voice, bradycardia, dry/rough skin, delayed tendon reflexes.
Elevated TSH, low T4, and low T3.Serum folate level is normal. Homocysteine levels are often elevated. [30]
Myelodysplastic syndrome
Gradual-onset fatigue often present, and 20% of patients have splenomegaly. May be associated with prior chemotherapy or radiation exposure.
Macrocytic anaemia may be associated with neutropenia and thrombocytopenia.Peripheral smear findings include dimorphic anaemia; large, hypogranular platelets; hypogranulated, hyposegmented neutrophils with Dohle bodies; and circulating myeloblasts.Bone marrow shows dyserythropoiesis; hypogranulated, hyposegmented granulocytic precursors; increased myeloblasts; and megakaryocytes showing fewer or disorganised nuclei. Ringed sideroblasts are seen in the bone marrow in certain sub-types of myelodysplastic syndrome.Cytogenetic analysis and fluorescence in-situ hybridisation can identify chromosomal abnormalities.
Aplastic anaemia
History of prior viral illness, chemical exposure, or drug use may be present.Bleeding, lassitude, and symptoms of infection are usually present. Ecchymosis and signs of infection may be present, in addition to pallor.
Macrocytic anaemia, neutropenia, thrombocytopenia, and reticulocytopenia are present.Bone marrow aspirate and biopsy show decreased cellularity and paucity of all 3 lineage precursors.
Pure RBC aplasia
Manifests usually during infancy, with pallor. FHx may be present.May be associated with abnormal phenotype, and with signs and symptoms related to cardiovascular and renal anomalies.
Macrocytic anaemia and reticulocytopenia are the hallmarks.Elevated erythrocyte adenosine deaminase is present in 70% to 80% of patients.Bone marrow examination shows isolated RBC hypoplasia or aplasia. Other cell lines are generally uninvolved.
Drug-induced macrocytosis
Associated with intake of certain drugs, such as cytotoxic drugs, immunosuppressive drugs, anticonvulsants, and antiviral medications.
Usually a clinical diagnosis.Serum folate level is normal.
Diphyllobothriasis
Presents with abdominal discomfort, diarrhoea, vomiting, weakness, weight loss, and occasionally acute abdominal pain due to intestinal obstruction, cholangitis, or cholecystitis. Additional features are megaloblastic anaemia and neurological abnormalities secondary to vitamin B12 deficiency.
Stool examination reveals characteristic eggs of the fish tapeworm Diphyllobothrium latum.Serum vitamin B12 levels are low.Serum folate is normal.

Folliculitis

Pseudofolliculitis barbae
Occurs when hair re-enters the skin adjacent to the exit point from the hair follicle.Occurs in men of African descent or other racial groups with dark, curly hair.Inflammatory papules develop in the beard area as well as the anterior neck in men who shave regularly.The mustache area usually does not develop pseudofolliculitis barbae.Postinflammatory hyperpigmentation often persists following resolution of active lesions. Chronic pseudofolliculitis barbae can lead to development of firm papules, plaques, hypertrophic scars, and groove formation in the anterior neck and submandibular areas.
The advancing end of a curved hair shaft reentering the epidermis results in a histological picture of an invagination of the epidermis.Accompanied by inflammation, and sometimes microabscess. When the hair enters the dermis, a more exuberant inflammatory response is elicited, and a foreign body giant cell reaction is formed around the tip of the hair.
Acne vulgaris
Can mimic folliculitis because both diseases affect the pilosebaceous unit.Although acne vulgaris is typically considered a condition of adolescence and early adulthood, it can persist later into adult life.Acne primarily affects the face, chest, shoulders, and the back. Comedones and inflammatory papules seen in acne are both follicular based.
Histopathology shows infundibular dilatation and thinning of the follicular wall with a follicular plug consisting of keratinised cells and sebum. When follicular contents are released into the dermis, there is an inflammatory response mediated by neutrophils and later by histiocytes.
Acne rosacea
Rosacea is an acneiform condition that occurs more commonly in people 30 years or older.Typically affects the nose, cheeks, glabella, and chin.Rosacea can present as diffuse redness with telangiectasia (erythrotelangiectatic subtype), papules and pustules (papulopustular subtype), View imageView image bulbous swelling of soft tissue (phymatous subtype), or even painful keratitis (ocular rosacea).
Histology of rosacea shows dilatation of vessels in the upper and mid-dermis with a lymphohistiocytic infiltrate around the hair follicles.
Alopecia mucinosa
Alopecia mucinosa is a condition where follicular mucinosis affecting terminal hair follicles ultimately results in hair loss.Although follicular papules may be present, some cases present with only well circumscribed patch of alopecia. [14]
Histology shows extensive mucin deposition within the outer root sheath and sebaceous gland epithelium, leading to reticular epithelial degeneration. [15]

Foodborne E coli infection

Viral gastroenteritis
Often associated with symptoms such as myalgia and arthralgia, although this is not an absolute rule.Unlikely to be a travel or food contact history.Often this occurs in outbreaks, especially in healthcare settings.Usually of shorter duration (24 to 48 hours).
No specific differentiating tests.Stool cultures may identify pathogen, but high rate of false negative results.
Alternative foodborne bacterial gastroenteritis/traveller's diarrhoea
Identical signs, symptoms, and contact risks.
Stool cultures will identify pathogen (e.g., salmonellosis, Shigella), but high rate of false negative results.
Amoebiasis
Onset is typically sub-acute, and patients often report diarrhoea that has lasted for several days or longer, together with abdominal pain and weight loss.
Stool microscopy reveals Entamoeba.Serum antibody testing positive for antiamoebic antibodies.
Non-infectious food poisoning
Examples include mushrooms or toxins.Often has an acute history, associated with consumption, with symptoms developing 1 to 12 hours later.Symptoms are dependent on the exact mushroom or toxin ingested and can be associated with nausea, vomiting, renal or hepatic failure.
Identification of the ingested substance.
Ulcerative colitis
Usually has a more chronic history, with slower deterioration.Symptoms vary from intermittent rectal bleeding associated with the passage of mucus to frequent loose, bloody stools.
Definitive diagnosis is made by colonic mucosal biopsy showing characteristic histological changes. Vascular markings are lost, owing to engorgement of the mucosa, giving it an erythematous appearance. In addition, petechiae, exudates, touch friability, and frank haemorrhage may be present. Colonic involvement is continuous.
Crohn's disease
Usually has a more chronic history, with slower deterioration, and prolonged diarrhoea, often accompanied by weight loss.
Definitive diagnosis is made by biopsy, which shows focal ulcerations adjacent to areas of normal-appearing mucosa, along with polypoid mucosal changes that give a cobblestone appearance. Pseudopolyps are also often present. May involve the entire GI tract from mouth to peri-anal area.
Non-infectious GI pathologies
Examples include diverticular disease, malignancy, or coeliac disease.These conditions are usually associated with a more chronic history (>4 weeks), and a lack of features of sepsis.Associated symptoms may aid diagnosis (e.g., weight loss in malignancy).
Dependent on underlying cause. The majority of conditions are diagnosed by endoscopy or by radiological exams (CT, MRI).

Food allergy

Atopic dermatitis
Pruritic, morbilliform, or maculopapular eruptions.
Selected allergens evaluated for specific IgE based on history.Rash in the predilection sites for atopic dermatitis within 1 hour of an oral challenge. [37]
Urticaria
Appearance not necessarily related to food ingestion (e.g., penicillins, sulphonamides, muscle relaxants, diuretics, NSAIDs).Erythematous oedematous lesions on any part of the body.Typically pruritic, although occasionally painful or burning sensation reported.Dissipates within 24 hours leaving no residual markings.Up to 40% of cases of urticaria have associated angio-oedema (swelling of the deeper layers of the subdermis).Foods are not the cause of chronic urticaria (lasting >6 weeks).
Lack of response to in vitro IgE testing or skin prick testing.Foods are not the cause of chronic urticaria (lasting >6 weeks).
Auriculotemporal syndrome
Recurrent episodes of facial flushing, sweating along the distribution of the auriculotemporal nerve.Occurs in response to gustatory stimuli. [38]
Diagnosis is clinical.
Acute asthma exacerbation in children
Fatigue, dyspnoea, exercise intolerance, aesthete body type, and wheezing, but seldom the only symptoms and signs. [39]
Pulmonary function testing with diminished FEV1.Greater likelihood of progression to irreversible obstructive airway disease.
Acute asthma exacerbation in adults
Dyspnoea; may be precipitated by allergens, cold, or exercise; wheezing reversible on administration of bronchodilators.
Pulmonary function testing with diminished FEV1.Greater likelihood of progression to irreversible obstructive airway disease.
Food-induced pulmonary haemosiderosis (Heiner's syndrome)
Recurrent pneumonia associated with pulmonary infiltrates, haemosiderosis, GI blood loss, iron deficiency anaemia, and failure to thrive. [2]In infants, most often caused by non-IgE-mediated hypersensitivity to cows' milk.
High titres of precipitating IgG antibodies to bovine milk proteins. [16]Chest x-ray with pulmonary infiltrates. [16]Symptoms improve with removal of cows' milk from the diet.
Tracheo-oesophageal fistula
Neonates.Regurgitation of feeding.Aspiration and pneumonia.
Chest x-ray with air-distended oesophageal atretic pouch; the nasogastric tube coiled in this pouch.Also, excessive dilation of stomach as a result of fistula communication. [40]
Pollen food syndrome (oral allergy syndrome)
Oropharyngeal pruritus and angio-oedema of the lips, oral mucosa, and soft palate. [41]Symptoms not likely to progress to systemic anaphylaxis.
Double-blind placebo-controlled food challenge.Skin prick testing or in vitro assays with suspected fresh fruit or vegetable.Causative allergens in fruits and vegetables have homologous proteins to pollens of grasses, trees, and weeds. [41]
Food protein-induced enterocolitis syndrome
Manifests in the first few months of life. Projectile vomiting, diarrhoea, and failure to thrive. [16]Associated with ingestion of cows' milk or soya protein.Similar syndrome presents in older infants and children as a result of egg, wheat, rice, oat, peanut, nuts, chicken, turkey, and fish sensitivity. Shellfish sensitivity may be causative in adults.
Oral food challenge will lead to vomiting within 1 to 4 hours after ingestion (caution: may cause severe hypotension).Elevation in peripheral blood neutrophils. [23]
Food protein-induced colitis
Presents in first few months of life. [16]Infants with isolated finding of blood in the stool.
Stool positive for blood in infants.
Eosinophilic oesophagitis/gastroenteritis
Postprandial nausea, gastro-oesophageal reflux, vomiting, abdominal pain, and early satiety. Weight loss and failure to thrive in children. [16]
Oesophageal or gastric biopsy shows dense eosinophilic infiltrates. [16]
Gastroenteritis in children
Persistent diarrhoea lasting from 1 to 8 days.Usually accompanied by fever.
Presence of faecal lymphocytes.Microscopy and stool culture positive for causative organisms.Elevated WBC if sepsis; blood cultures positive for causative organisms.Clostridium difficile toxin present (i.e., in patients with recent prolonged antibiotic use).
Gastroenteritis in adults
Persistent diarrhoea lasting from 1 to 8 days. Usually accompanied by fever.
Presence of faecal lymphocytes.Microscopy and stool culture positive for causative organisms.Elevated WBC if sepsis; blood cultures positive for causative organisms.Clostridium difficile toxin present (i.e., in patients with recent prolonged antibiotic use).
Irritable bowel syndrome
Recurrent abdominal pain or discomfort that is associated with a change in stool frequency or form.Mild and poorly localised tenderness in the RLQ and/or LLQ.
Diagnosis is clinical and by exclusion of other causes (e.g., Crohn's disease, ulcerative colitis).
Crohn's disease
FHx of Crohn's disease; more common in white people than in black or Asian people; age 15 to 40 years or 60 to 80 years.Crampy or constant abdominal pain with non-bloody, intermittent diarrhoea.Perianal lesions (e.g., skin tags, fistulae, abscesses, scarring) may be present.
Abdominal radiography with small bowel or colonic dilation; calcification; sacroiliitis; intra-abdominal abscesses.CT and MRI with skip lesions, bowel wall thickening, surrounding inflammation, abscess, fistulae.Bowel biopsy histology demonstrates transmural non-caseating granulomas.
Ulcerative colitis
Diarrhoea and haematochezia.Cramps, anorexia, weight loss, mild anaemia, malaise, and low-grade or intermittent fever. [42]
Abdominal radiography with dilated colon, intra-abdominal free air, perforation.Colonic biopsy histology of acute and chronic inflammation with polymorphonuclear leukocytes infiltrating the submucosa. [42]
Hiatal hernia
Intolerance to spicy or acidic foods, particularly with recumbency and after retiring for the evening.Mid-epigastric to lower thoracic discomfort relieved with prolonged sitting position or elevation of head of bed.Specific lack of cutaneous or respiratory symptoms.
Diagnosis is primarily clinical.Upper GI series with gastric cardia herniated 2 cm above the hiatus.
Pyloric stenosis
Vomiting, failure to thrive.Pyloric mass. [43]
Abdominal ultrasound with pyloric thickness >4 mm or an overall pyloric length >14 mm. [43]
Hirschsprung's disease
Abdominal distention and stool retention.Toxic megacolon, peritonitis, perforation.
Barium enema demonstrates segmental narrowing with ballooning of the proximal part of the bowel.Rectal/colon biopsy absence of ganglion cells.
Pancreatic insufficiency (e.g., cystic fibrosis)
Chronic diarrhoea.Steatorrhoea.
Elevated sweat chloride levels (>60 mmol/L) in cystic fibrosis.
Gastro-oesophageal reflux disease
Heartburn.Hiatal hernia and advancing age.Acidic reflux into oral cavity.Absence of cutaneous or respiratory involvement.
Diagnosis is clinical.A therapeutic trial of a proton-pump inhibitor can serve for both diagnosis and initial treatment.
Cholecystitis
RUQ or epigastric abdominal pain. [44] Pain may radiate to the right shoulder or back and is usually steady and severe.Associated symptoms: nausea, vomiting, and anorexia.Often a history of fatty food ingestion about 1 hour or more before initial onset of pain.
Elevated leukocytes with a left shift on FBC.Ultrasound or cholescintigraphy may be needed to confirm the diagnosis. [44]
Coeliac disease
Persistent diarrhoea with gluten ingestion.Presence of dermatitis herpetiformis.
Low Hb and microcytic red cells on FBC.Immunoglobulin A-tissue transglutaminase (IgA-tTG) titre above normal for laboratory.Endomysial antibody (EMA) titre elevated.Biopsy of the small bowel helpful when positive, but a negative result does not rule out the disease.Human leukocyte antigen DQ2DQ8 testing is highly sensitive (90% to 95%) for coeliac disease but not very specific.
Food poisoning (e.g., Clostridium botulinum, Staphylococcus aureus, Escherichia coli)
Abdominal pain, nausea, vomiting.Fever may appear from 1 to 72 hours after ingestion. [43]
Faecal leukocytes present and stool culture grows organism.Blood cultures grow organism.
Alcohol overdose
In early acute intoxication, euphoria, giddiness, and loss of inhibitions. [30] Nausea, vomiting, abdominal pain, facial flushing, ataxia, and diminished reflexes.In late acute intoxication, CNS depression becomes generalised, leading to ataxia, nystagmus, slurred speech, and sedation. May progress to coma, loss of protective airway reflexes, autonomic dysfunction, hypothermia, death.
With acute intoxication an elevated blood alcohol level is detectable.
Lactose intolerance
Typically 8 to 15 years of age.Crampy abdominal pain, bloating, and acidic diarrhoea. [45]
Trial elimination diet therapeutic.Positive hydrogen breath test, defined as a rise in breath hydrogen >20 ppm within 90 minutes of ingestion of 50 g of lactose. [45]
Toxic reactions (e.g., scombroid poisoning, ciguatera poisoning, saxitoxin)
Cutaneous symptoms of prolonged flush in the absence of urticaria.Several people dining from the same meal may experience symptoms. [16]
Normal serum tryptase and elevated histamine. [16]May have normal serum tryptase and histamine in IgE-mediated responses.
Accidental contamination (pesticide or antibiotics)
Excessive salivation, lacrimation, bronchorrhoea, urinary and faecal incontinence, and vomiting. [46]
Atropine (1 to 2 mg intravenously as a single dose) is given as a therapeutic trial in all suspected cases or when diagnosis is in doubt. Lack of anticholinergic response is positive test.Plasma cholinesterase and RBC cholinesterase used to confirm diagnosis.Specific IgE may be present with inadvertent allergy to antibiotic ingested.
Fungal toxins (e.g., aflatoxins, trichothecenes, ergots)
Fever, malaise, vomiting, and jaundice. [47]
Absence of specific IgE.
Caffeine overdose
Overdose may lead to agitation, vasoconstriction, tremor, and hypertension. [46]
Diagnosis is clinical.
Theobromine (e.g., tea, chocolate) intoxication
Nausea, vomiting, anxiety, nervousness, and insomnia are evident in mild intoxication. Seizures occur in severe poisonings. [46]
Diagnosis is clinical.
Serotonin (e.g., banana, tomato) overdose
Diarrhoea, headache, and fatigue if ingested in large amounts. [48]
Diagnosis is clinical.
Food phobias/aversions
May mimic adverse food reactions.
Absence of specific IgE.Double-blind placebo-controlled food challenge (DBPCFC).Symptoms are not reproducible with DBPCFC. [16]

Food poisoning

Acute viral syndromes
Very difficult to differentiate; lack of exposure to specific foods or absence of specific behaviours may help in differentiating.
Occasionally, acute viral serology, in particular IgM, (presence or rise from baseline) may help diagnose specific viruses.
Inflammatory bowel disease (IBD)
Initial presentation may be acute and mimic inflammatory diarrhoea caused by invasive pathogens.Protracted course together with systemic symptoms may help differentiate.
Colonoscopy with biopsies and IBD serological markers helps in differentiation.
Food allergies/intolerance
History of exposure to certain foods known to cause intolerance or allergies (milk, lactose, gluten) and relapsing symptoms with challenge.
Coeliac markers are positive in most patients with gluten intolerance.Hydrogen breath test helps in diagnosing lactose intolerance.Colonoscopy and biopsies help in diagnosing milk allergies.
Irritable bowel syndrome (IBS)
Total duration of symptoms should be more than 6 months with specific criteria of combination of abdominal bloating or pain relieved by defection and association with change in stool frequency and/or consistency without evidence of alarm signs or symptoms.Physical examination reveals a healthy non-toxic appearance without evidence of dehydration.
All imaging and laboratory tests are usually within normal range.
Microscopic colitis
Typically present in older persons, long duration symptoms and lack of haematochezia or blood in stool.
Colonoscopy revealing normal appearing mucosa and biopsies sowing lymphocytic infiltrates and/or thickened collagenous layer are diagnostic.
Acute appendicitis
Localised right lower quadrant pain and peritoneal irritation are classic (guarding).
CT scan of the abdomen is diagnostic.Elevated serum and urine WBCs.
Acute cholecystitis
Localised pain in RUQ and a positive Murphy sign are classic symptoms.
Ultrasound showing gallbladder wall thickening, elevated alkaline phosphatase, bilirubin ALT and AST when biliary obstruction is present (choledocholithiasis).
Acute pancreatitis
Epigastric pain radiating to the back, history of excessive alcohol consumption in alcohol induced pancreatitis may help.
Elevated serum amylase and lipase and CT scan findings are diagnostic.
Acute hepatitis
Jaundice is usually present.Risk factors for acute hepatitis B and C include unprotected sex and IV drug use.History of excessive alcohol consumption in alcoholic hepatitis.History of hepatotoxic medication use or overdose in drug induced hepatitis.Neurological signs and Kayser-Fleischer ring in Wilson's disease.
Serology for acute hepatitis (acute hepatitis panel), serological markers of autoimmune hepatitis, serum ceruloplasmin, drugs level in particular acetaminophen can help.When leukopaenia and thrombocytopaenia present, tick-born/rickettsial infections (Rocky Mountain spotted fever and Ehrlichia) are considered.
Malabsorption syndromes
Chronic symptoms and significant malnourishment, history of intestinal surgery and extraintestinal manifestations of malnourishment and malabsorption are usually present.
Stool alpha antitrypsin, low serum prealbumin, albumin and total protein, multiple vitamins and elements deficiency.
Bowel obstruction
Abdominal distention and pain and history of abdominal surgery.Lack of history suggestive of food poisoning.
Distended bowel loops and air-fluid levels on acute abdominal series plain films. However, food poisoning may be associated with ileus and functional obstruction and same imaging findings.
Radiation enteritis
Patients have a history of receiving radiation therapy.
Endoscopy and biopsy; histological findings support this diagnosis.
Mesenteric ischaemia
Occlusive or nonocclusive (the latter causes more chronic symptoms mainly postprandial).
CT scan/endoscopy. Typical finding is thickening of the bowel wall in a segmental pattern.Endoscopic findings include pale mucosa with petechial bleeding. Bluish haemorrhagic nodules may be seen representing submucosal bleeding; these correspond to thumbprints seen on radiographic studies.
Medication and drugs side-effects/toxicity
History of drugs ingestion/use.
Urine and serum screen, blood drug level.
Diverticulitis
Leukocytosis and fever in an older patient.
CT scan/WBC.
Systemic vasculitis
Multisystem involvement (skin, joints, blood) and chronic presentation.
Biopsy shows vasculitis pattern (leukocytoclastic, necrotising).

Foreign body aspiration

Asthma exacerbation
Wheezing is paroxysmal, intermittent, usually diffuse, and decreases after bronchodilators. Wheezing is polyphonic, characterised by many different pitches. Cough is more prominent in asthma than in foreign body aspiration, and is triggered by exercise, cold, sleep, and allergens; there is a personal and/or family history of atopy or asthma. [33]
Chest x-ray shows peribronchial cuffing and hyper-inflation, but does not rule out foreign body aspiration. Pulmonary function tests usually show reversible obstructive ventilatory impairment. [33]
Cystic fibrosis with exacerbation
Wheezing presents early in life; poor weight gain, diarrhoea, and recurrent sinus and pulmonary infections; nasal examination may reveal polyps. Cough is productive and 'wet,' suggesting a suppurative process such as bronchiectasis; there may be a family history of bronchiectasis. [33]
Sweat chloride test; chest x-ray may reveal bronchiectasis, but CT scan is more sensitive. [34]
Acute COPD exacerbation
Wheezing is diffuse, associated with increased mucous production and progressive dyspnoea.
Chest x-ray shows peribronchial cuffing and hyper-inflation, but does not rule out foreign body aspiration. Pulmonary function tests reveal obstructive ventilatory impairment.
Croup
Seen in children from 6 months to 4 years old. [35] The cough is characteristically described as having a barky, seal-like pattern and is often accompanied by stridor and chest wall or sternal in-drawing. Symptoms are typically worse at night, and increase with agitation.
Diagnosis made on clinical grounds. Subglottic oedema may be seen on x-ray or at laryngoscopy, if performed.
Epiglottitis
Patient may have high fever, sore throat, dysphonia, muffled voice, drooling, and dysphagia, in addition to stridor and dyspnoea. [35] The child may assume the 'tripod position' - sitting up with the neck extended and leaning forwards with the jaw thrust out.
Lateral neck x-ray can show the swollen epiglottis and aryepiglottic folds 'thumb sign', but should be done only in case of doubt and after the airway is secured. [35]
Central airway obstruction
Wheezing is slowly progressive and unilateral in cases of obstruction distal to the main carina. Neonatal onset of cough suggests congenital tracheobronchomalacia. [33] [36]
Chest x-ray may show tracheal or bronchial narrowing; chest CT scan provides details about the mediastinum, and is able to localise and quantify the degree of airway obstruction. [36]
Infectious pneumonia
Fever, rales, tachypnoea, and cough productive of frothy or purulent sputum may occur if infection supervenes after foreign body aspiration.
Chest x-ray may show lobar consolidation.

Foreign body ingestion

Epiglottitis/supraglottitis (in children)
Dysphagia, muffled voice, and difficulty handling oral secretions.
Swab cultures from epiglottis, trachea, or nasopharynx usually yield a predominant growth of Haemophilus influenzae type B (Hib).
Peritonsillar abscess (in children)
Spiking fever, neck pain/torticollis, neck swelling/mass/lymphadenopathy.
CT shows a ring-enhancing lesion in the retropharyngeal tissues when performed with contrast.
Pyloric stenosis or hypertrophic pyloric stenosis (in children)
Non-bilious projectile vomiting. Firm, non-tender, and mobile structure (described as an 'olive') is palpable in the right upper quadrant.
Electrolyte abnormalities (hypochloraemia and hypokalaemic metabolic alkalosis) are seen. Ultrasound shows pyloric muscle thickness of >4 mm and pyloric canal length of >17 mm, the diagnostic criteria for full-term infants. [36]
Oesophagitis
Retrosternal chest pain, pyrosis, coffee ground emesis, anorexia, weight loss, cough, fever, and sepsis.
Oesophagogastroduodenoscopy is the diagnostic test of choice, allows mucosa visualisation, brushing, and biopsy of the lesions.
Small bowel obstruction
Colic-like pain (cramping and intermittent), with spasm lasting a few minutes. Pain is usually localised in the centre or mid-abdomen. Vomiting may occur.
Radiography, abdominal ultrasound, CT scan of the abdomen, magnetic resonance imaging (MRI) and/or endoscopy (single or double balloon) to show obstruction. Biopsy may be indicated in some cases.
Colonic obstruction
Pain in the lower abdomen (infraumbilical, left lower quadrant or right lower quadrant). Diarrhoea or constipation with or without haematochezia may be present.
Radiography (plain film or with contrast material), abdominal ultrasound, CT scan of the abdomen, MRI or flexible sigmoidoscopy, or full colonoscopy to show obstruction. Biopsy may be indicated in some cases.

Frontotemporal dementia

Alzheimer's disease (AD)
CT shows global atrophy in AD, and focal atrophy in FTD. However, structural MRI typically shows regional losses in the temporoparietal regions in AD and the temporofrontal regions in FTD.The physical examination does not reliably distinguish the conditions, because a normal examination is usually noted. One key feature that may differentiate FTD from AD is relative preservation of memory.
CT/MRI shows global atrophy in AD, and focal atrophy in FTD.Single photon emission computed tomography (SPECT) or PET in early AD generally shows abnormality in the posterior cingulate and parietal lobes. [28]
Dementia with Lewy bodies (DLB)
DLB is characterised by predominance of amnesia, fluctuation in cognition, visual hallucinations, and parkinsonism in the early stages of the illness.Personality and comportment are relatively preserved.Visual hallucinations are very rare in FTD. [29]
CT/MRI shows global atrophy in DLB, and focal atrophy in FTD.SPECT or PET in early DLB generally shows abnormality in the parietal and the occipital lobes. [28]
Bipolar disorder
Episodes of mania and depression typically begin in the third decade of life and show complete remission between episodes. When late-onset mania occurs after age 60 years it is attributable to brain diseases (cerebrovascular, trauma, neoplasm, drug withdrawal and/or intoxication) in >80% of cases.
Brain imaging is generally normal in bipolar disorder.
Major depression
Major depression is characterised by the marked predominance of sad mood, anhedonism, hopelessness, suicidal thoughts, retardation, insomnia, and self-deprecating and pessimistic mental states. Most likely to be confused with the apathetic type of FTD.
Brain imaging is usually normal in major depression.
Obessive-compulsive disorder (OCD)
In OCD onset is typically in the second and third decades of life. Remission may not be complete between episodes but OCD can be distinguished by long history and association of compulsions with preserved insight and marked anxiety. Patients with early onset dementias often try to cope with their cognitive impairment by imposing order on the threat of chaos.
Brain imaging is generally normal in OCD, and shows regional atrophy, hypo-perfusion, or hypo-metabolism in FTD.
Substance abuse disorders
States of intoxication from stimulants, alcohol, and other agents may mimic FTD by producing euphoria, disinhibition, impulsiveness, and poor judgement, but these states are usually transient.Track marks and puncture sites may be visible on arms, legs, and neck, along the course of superficial veins.
Serum and urine toxicology will usually identify the substance abused.
Vascular dementia
Vascular dementia may mimic FTD by presenting with prominence of apathy, executive dysfunction or behavioural disorder (impulsiveness and irritability), and relative preservation of memory.
Brain CT or MRI will show evidence of cerebrovascular accident; lacunes in the basal ganglia and thalamus; or marked gliosis of the frontal, sub-cortical, and deep white matter.
Primary brain tumour
The cognitive manifestations of brain tumour depend on their location.Tumours in the frontal lobes may present with decreased attention and alertness, executive dysfunction, and impaired social judgement.Tumours in the temporal lobes may present with non-fluent aphasia and memory disorder.
Brain imaging will show tumour, and may also show a penumbra of oedema and compression of adjacent brain structures.
Hyperthyroidism
Features of hyperthyroidism, such as irritability, restlessness, increased eating (with decreased satiation), and distractibility, may result in a presentation that mimics FTD
In hyperthyroidism, analysis of blood levels typically shows elevated levels of TSH and very low levels of free T4.

Frostbite

Cutaneous burns
Caused by exposure to heat or chemicals rather than cold. [1] [7]
Clinical diagnosis.
Frostnip
Milder than frostbite. Symptoms of numbness or pain are present with no evidence of actual tissue damage. [1]
Clinical diagnosis.
Raynaud's phenomenon
Skin changes are reversible.No evidence of tissue damage. [1]
Clinical diagnosis.
Pernio (chilblains)
Erythema with reactive hyperaemia is the dominant symptom.Purplish discoloration is absent.
Clinical diagnosis.
Immersion foot (trench foot)
A non-freezing injury caused by prolonged exposure to cold and wet environment, usually 1°C to 4°C (34°F to 39°F). View image
Clinical diagnosis.

Fungal meningitis

Tuberculous meningitis
History of contact, or resident in endemic area.Symptoms and signs of pulmonary and extraneural disease.
CSF smear and culture. Sensitivity of smear >50% if repeated drops of CSF sediment dried on a slide and then stained and examined at length. [59] Culture requires large volume for maximum sensitivity.Skin testing or IFN-gamma-based blood tests for exposure to Mycobacterium tuberculosis supportive; but negative results do not exclude diagnosis of TB.
Bacterial meningitis
Relevant exposure history.May be difficult to distinguish clinically with symptoms and signs including meningismus, headache, myalgias and pharyngitis.
Specific serology (Borrelia burgdorferi, Brucella, Leptospira, Treponema pallidum).Culture (Actinomyces, Nocardia, Brucella).Partially treated disease confirmed with non-culture diagnostic methods: PCR, antigen tests for meningococcal and pneumococcal infection.
Viral meningitis
Relevant exposure history.May be difficult to distinguish clinically with symptoms and signs including meningismus, headache, myalgias and pharyngitis.
Serology for herpes simplex virus, varicella zoster virus and other viruses; CSF viral culture; PCR for enteroviruses and herpes viruses.
Non-infectious lymphocytic meningitis
History, symptoms, signs suggestive of autoimmune, sarcoidosis, systemic lupus, Behcet's disease, carcinomatous meningitis.Recurrent chemical meningitis may be associated with epidermoid cysts or craniopharyngioma.
Head CT/MRI imaging may demonstrate epidermoid cysts or craniopharyngioma.CSF cytology may demonstrate malignant cells; CSF angiotensin converting enzyme (ACE) elevated in sarcoidosis.Autoantibodies to investigate systemic manifestations.

Ganglion cyst

Carpal tunnel syndrome
Paraesthesia in the thumb, index, and long finger typically worse at night (patients with ganglion cysts rarely describe paraesthesia). This may awaken the patient from sleep. With advanced cases, weakness of the hand and difficulties with fine motor tasks may become evident.Physical examination can reproduce the symptoms of paraesthesias by direct compression of the median nerve at the volar wrist crease or placing the patient in a position of wrist flexion for up to 1 minute. Typically, a Tinel sign is present with tapping over the median nerve at the wrist.
Electromyelographic evaluation will show focal slowing of conduction velocity in the median sensory nerves across the carpal tunnel; prolongation of the median distal motor latency; possible decreased amplitude of median sensory and/or motor nerves.
Lipoma
Does not trans-illuminate. Mass usually not entirely spherical.
Aspiration does not yield any fluid.Ultrasound demonstrates a non-cystic mass.MRI demonstrates a well-circumscribed mass with increased signal intensity on T1-weighted image.
Giant cell tumour of the tendon sheath
Mass is more solid and does not trans-illuminate. Mass is fixed to the underlying tendon sheath and is therefore is less mobile than a ganglion cyst.
Aspiration does not yield fluid.MRI or ultrasound confirms solid tumour located adjacent to tendon sheath.
Tenosynovitis
Diffuse swelling and bogginess of the tenosynovium overlying the tendons. Usually tracks along the tendon in a longitudinal fashion, not a discrete mass. Can have transverse band-like pattern across the wrist.
Aspiration does not yield any fluid.MRI demonstrates increased fluid uptake along the tendons, not a well-defined cystic structure.
Carpal instability
Disruption of the normal carpal kinematics usually preceded by trauma to the wrist. Can result in a change in lunate position where the proximal pole of the scaphoid can be palpated. No trans-illumination, compressibility, or movement of the mass on examination.
Radiographs demonstrate a dorsally or volarly angulated lunate with regards to the capitate, and a widening of the scapholunate or lunotriquetral joint space.
Osteoarthritis
Usually pre-existing arthritic conditions, typically of the scaphotrapeziotrapezoid joint.Palpable hard, firm, non-cystic, non-mobile mass which does not trans-illuminate.
PA and lateral view radiographs of the wrist show degenerative changes (osteophyte or arthritic surfaces of the scaphotrapeziotrapezoid joint).
Radial artery aneurysm
Mass may be pulsatile and a thrill palpated. Does not trans-illuminate.
Aspiration may yield arterial blood and is not recommended.Ultrasound with Doppler flow will demonstrate blood flow within the structure.
Posterior interosseous nerve neuroma
Mass not as freely mobile (anchored to posterior interosseous nerve in posterior aspect of the wrist) and does not trans-illuminate.
Aspiration does not yield any fluid.Ultrasound demonstrates non-cystic mass.MRI demonstrates mass without increased signal intensity on T2-weighted image.
Soft tissue sarcoma
Typically not well circumscribed nor as freely mobile (can be difficult to distinguish given the varied presentation of sarcomas).
Referral to specialised centre recommended for aspiration or biopsy.MRI helps determine lesion location and varied characteristics. May show ring enhancement or varied signal intensity.
Osteosarcoma
Typically not well circumscribed or mobile (can be difficult to distinguish given the varied presentation of sarcomas).
Referral to specialised centre recommended for aspiration or biopsy.MRI helps determine lesion location and varied characteristics. May show ring enhancement or varied signal intensity.
Septic arthritis
Typically presents with an erythematous, warm, swollen joint. There is pain associated with minimal motion of the radiocarpal joint. An effusion can often be detected.
Difficult to differentiate from crystalline arthropathy without joint aspiration.White cell count, ESR, and C-reactive protein levels usually elevated.Joint aspiration will yield purulent material with increased neutrophil count and typically bacteria on Gram stain and culture.
Crystalline arthropathy
Typically presents with an erythematous, warm, swollen joint. There is pain associated with motion of the radiocarpal joint. An effusion can often be detected.
Difficult to differentiate from septic arthritis without joint aspirationUric acid levels usually elevated. Aspiration of the joint will yield crystals on polarised microscopic examination.
Old trauma
Previous history of injury of the wrist or carpus may cause malunited fractures with palpable deformity or ligament disruptions resulting in carpal instability.
PA and lateral view radiographs of the wrist help detect previous traumatic events. Bony malunion of fractures, degenerative disease, or signs of carpal instability may be present.

Gangrene

Staphylococcal skin lesions
Distinct pustules, subcutaneous abscesses, purulent purpura often present in this condition. [1]
Blood culture: positive for staphylococcal infection.Aspiration and microscopy: reveals staphylococci and polymorphonuclear leukocytes. [1]
Erysipelas
History of recent pharyngitis. Infants and older people are usually affected. Pruritus and burning are present before the dermatosis. [1] Sharply delineated, painful lesion with a bright red, oedematous, indurated (peau d'orange) appearance. Bullae only in 5% of cases.
Antistreptococcal antibodies may be detectable.
Cellulitis
Absence of purple or red bullous lesions, absence of crepitus, intact sensation distal to the affected area, and comparatively slow spread. Systemic toxicity (e.g., renal failure, hypotension, and acidosis) usually absent with cellulitis.
Serous discharge may be expressed on compression of the wound margins, and streptococci can be identified on a Gram-stained smear. [1]Imaging studies (radiography, CT, and MRI): absence of the gas, fascial enhancement, and soft-tissue oedema characteristic of gangrene.
Insect bites
History of insect or spider bite, or suitable clinical scenario. The bite of the brown recluse spider (Loxosceles reclusa) can produce a necrotising skin lesion that resembles infectious gangrenous cellulitis. Fever is not commonly present, but the occurrence of fever and chills 24 to 48 hours after the bite enhances the mimicry. [1]
Clinical diagnosis.

Gastritis

Peptic ulcer disease
Clinical signs and symptoms may be similar.
Peptic ulcer disease is strongly associated with Helicobacter pylori infection and NSAID use. [4]Faecal occult blood test may be positive, indicating occult GI bleeding.Endoscopy shows presence of peptic ulcer.
GORD
Clinical signs and symptoms may be similar.
H pylori urea breath test is negative.Endoscopy shows oesophageal involvement.
Non-ulcer dyspepsia
Clinical signs and symptoms may be similar.
H pylori urea breath test is negative. [28] [29]Endoscopy is normal.
Gastric lymphoma
Clinical signs and symptoms may be similar.
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is strongly associated with H pylori infection. [4] Faecal occult blood test may be positive, indicating occult GI bleeding.Endoscopy may show presence of ulcer. Biopsy histology shows abnormal lymph follicle architecture with variable number of blast cells.Molecular cytogenetics (e.g., reverse transcriptase PCR or fluorescence in situ hybridisation may show characteristic t(11;18) translocation within lymphoid cells).
Gastric carcinoma
Patient may have suspicious features (e.g., bleeding, anaemia, early satiety, unexplained weight loss [>10% body weight], progressive dysphagia, odynophagia, or persistent vomiting).
Gastric carcinoma is strongly associated with H pylori infection and chronic gastritis. [4]Endoscopy shows gastric mass or irregular ulcer. [32]Biopsy reveals gastric carcinoma, most commonly adenocarcinoma.

Gastro-oesophageal reflux disease

Functional oesophageal disorder/functional heartburn
No reliable differentiating signs or symptoms.
Functional heartburn denotes endoscopy-negative heartburn by definition. A normal oesophageal pH study differentiates between non-erosive GORD and functional heartburn. An alternative is a normal impedance-pH study. These studies would usually be done in patients who fail to respond to proton pump inhibitor (PPI) therapy.
Achalasia
Dysphagia is typically prominent.
Oesophageal manometry and/or oesophagram are abnormal and consistent with achalasia.
Biliary colic
Typically pain is located in the right upper quadrant/epigastrium.Pain is usually sudden in onset and increases in severity over 15 minutes, lasting from 30 minutes to 6 hours.It is dull and constant in nature and may radiate to the back/right subscapular area.
An ultrasound may show gallstones.
Non-ulcer dyspepsia
At least 3 months of recurrent upper abdominal pain, bloating, and nausea, with no obvious structural cause. [28]
No definitive differentiating tests. Oesophagitis is absent on endoscopy for both non-erosive GORD and non-ulcer dyspepsia, while peptic ulcer disease was excluded.
Peptic ulcer disease
Burning pain in the epigastrium, which occurs hours after meals or with hunger.The pain often wakes the patient at night and is relieved by food and antacids.
Endoscopy demonstrates ulcer.Testing for Helicobacter pylori infection is often positive, although not diagnostic.
Eosinophilic oesophagitis
Features of GORD and eosinophilic oesophagitis overlap. However, patients with eosinophilic oesophagitis may have younger age, symptoms of dysphagia, food impactions, or documented food allergies. [29] [30]
Endoscopy may show oesophageal rings, linear furrows, white plaques, exudates, absence of a hiatus hernia, and a narrow-calibre oesophagus. [29] [30]Maximum peripheral eosinophil count may be higher than typical for GORD. [30]Eosinophil count may be ≥15 per high power field in sampled oesophageal tissue. [29]There may be eosinophil degranulation in biopsy specimens. [30]
Malignancy
Suspected in older adults presenting with alarm symptoms: anaemia, acute or progressive dysphagia, haematemesis, melaena, onset of dyspepsia (if patient is >55 years of age), persistent vomiting, or involuntary weight loss (>5% body weight). [5]
Laboratory tests may show anaemia or abnormal LFTs.
CAD
Cardiac chest pain is typically substernal, precipitated by exertion, and relieved by rest.
ECG may show ST changes or Q waves.Exercise stress testing may abnormal.

Gastroparesis

Acute pancreatitis
Sudden onset of abdominal pain radiating to the back, epigastric tenderness, fever, and tachycardia.Nausea, vomiting, history of cholelithiasis, and alcohol intake are often present.
Serum amylase and/or lipase: elevated.Arterial blood gas: may show hypoxaemia and acid-base disturbances.Abdominal plain x-ray: may show a sentinel loop (isolated dilation of a segment of gut) adjacent to the pancreas, gas distending the right colon that abruptly stops in the mid or left transverse colon (cut-off sign), or calcifications.
Cyclic vomiting syndrome (CVS)
Recurrent, stereotypical episodes of nausea and vomiting associated with severe epigastric pain. [60] [61]Nausea and vomiting occurs intermittently as opposed to chronically.
Gastric emptying scintigraphy: normal. [60]
Functional dyspepsia
Common clinical condition with chronic symptoms of postprandial nausea, vomiting, fullness, epigastric pain, and bloating. [62] Symptoms are very similar to gastroparesis and it is difficult to distinguish these entities based on symptoms alone.
Gastric emptying scintigraphy: often normal. [63]
Gastric outlet obstruction
Mechanical obstruction in the distal stomach caused by a variety of conditions including pyloric stenosis and pancreatic cancer.Symptoms of gastric outlet obstruction are very similar to gastroparesis.
Gastric emptying scintigraphy: typically delayed.Upper gastrointestinal endoscopy or imaging studies such as upper gastrointestinal series or CT scan of the abdomen: evidence of mechanical obstruction in the distal oesophagus.
Rumination syndrome
Regurgitation of recently ingested food into the mouth. [64] [65] Food is regurgitated within minutes of eating in rumination as opposed to a slightly longer time phase between ingestion of food and vomiting in gastroparesis.Nausea is typically absent in rumination.
Gastric emptying scintigraphy: typically normal. [64]
Irritable bowel syndrome (IBS)
Chronic condition characterised by abdominal discomfort, bloating, and altered bowel movements (either constipation or diarrhoea, or both).Nausea and vomiting are atypical symptoms for patients with IBS. However, co-existing gastroparesis should be ruled out in patients with IBS, in whom nausea and vomiting are significant symptoms.
Upper and lower gastrointestinal endoscopy, and abdominal imaging studies: unremarkable.
Crohn's disease
Altered bowel movements (usually diarrhoea) and haematochezia.Small bowel obstruction should be ruled out in patients with fibrostenotic Crohn's disease and postoperative adhesions who have a recent onset of severe nausea and vomiting.
Colonoscopy with intubation of the ileum: shows aphthous ulcers, hyperaemia, oedema, cobblestoning, and skip lesions.
Ulcerative colitis
Altered bowel movements (usually diarrhoea) and haematochezia.
Flexible sigmoidoscopy: shows rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas (rarely seen), and normal terminal ileum (or mild 'backwash' ileitis in pancolitis).

Gender identity disorders

Autogynephilia
Male patient seeks hormone treatment and/or surgery to obtain female bodily characteristics (usually breasts) but either does not want to change social gender role to female or makes no more than token gestures in this regard.Often a greater degree of earlier sexual activity than in transsexualism, and a sexualised element to the desire for female characteristics (which may not be admitted).
No distinguishing tests: diagnosis is clinical.
Dysmorphophobia
Patient abhors and seeks the removal of either primary or secondary sexual characteristics but has no sense of membership of the opposite sex or desire to be taken as a member of the opposite sex.Aside from this preoccupation, function in birth gender role has often been quite good.
No distinguishing tests: diagnosis is clinical.
Ego-dystonic sexual orientation
Patient's main motivation is an intimate relationship with someone of the same birth sex.Patient has very negative views about homosexuality and seeks medical explanation and legitimisation of this desire.
No distinguishing tests: diagnosis is clinical.
Psychosis
Patient's presentation has the psychological texture of a delusion. Patient is not very worried about how well others perceive him/her as a member of the opposite sex.Often a history of psychosis or delusions. Sometimes negative symptoms or affective symptoms present at the time of interview.
No distinguishing tests: diagnosis is clinical.
Fetishistic transvestism
Wearing of the clothes of the opposite sex is associated with sexual arousal. The clothes are often sexualised. The behaviour may be accompanied by masturbation. After orgasm there is often a sense of shame and the rapid removal of the clothes, accompanied by a (transitory) resolution never to cross-dress again.Found almost exclusively in males.
No distinguishing tests: diagnosis is clinical.
Borderline personality disorder
Sense of identity is generally unclear, not isolated to gender identity. Beliefs about a variety of aspects of identity are intense but shallow and sometimes brief.Other aspects of personal history are consistent with personality disorder, and this diagnosis may have already been made. Gender dysphoria is of recent onset but very intensely presented.
No distinguishing tests: diagnosis is clinical.

Generalised anxiety disorder

Panic disorder
Characterised by recurrent episodes of sudden onset of anxiety, with at least 4 symptoms including shortness of breath, palpitations, shakiness, nausea, hot or cold flushes, dizziness, and fear of dying. Panic may exist along with GAD.Strong autonomic and physical complaints without the predominant picture of worry. [1]
No differentiating tests exist.
Social phobia
Anxiety or persistent fear is limited to social situations and fear of social scrutiny or embarrassment. [1]
No differentiating tests exist.
Obsessive-compulsive disorder
Anxiety is directly related to compulsions or obsessions.
No differentiating tests exist.
Post-traumatic stress disorder
Anxiety is directly related to exposure to reminders of past trauma.
No differentiating tests exist.
Somatoform disorders
Anxiety is directly related to specific physical complaints.Thorough medical evaluation shows no basis for physical complaints.
No differentiating tests exist.
Depression
Inability to feel pleasure with an overall sad or irritable mood. [1] [28]
No differentiating tests exist.
Substance- or drug-induced anxiety disorder
Anxiety is directly related to exposure to substance (e.g., caffeine, toxin, alcohol, illicit drug), drug (e.g., salbutamol, theophylline, corticosteroid, antidepressant), or herbal medicine (e.g., ma huang, St. John's wort, ginseng, guarana, belladonna).Thorough history of prescribed and over-the-counter medications and herbal medicines should be obtained. [28]A history of illicit drug and alcohol use should also be obtained.
Urine drug screen may identify substance abuse, such as intoxication with stimulants or withdrawal from alcohol or benzodiazepines. May miss cocaine, which is rapidly metabolised and excreted.Urine drug screen for antidepressants may detect prescribed medications or those taken in overdose.Serum theophylline level may be elevated above the therapeutic range.No differentiating tests exist for other substances or drugs.
CNS-depressant withdrawal
Anxiety may occur during withdrawal of a substance (e.g., alcohol, opioids, sedative-hypnotics) with characteristic symptoms such as shakiness (i.e., rapid heart rate, fluctuating blood pressure), and, if delirium is present, mental confusion.Typical signs on are tachypnoea, tachycardia, and disorientation.
Monitoring of vital signs is essential to detect autonomic instability and sometimes delirium.
Anorexia nervosa
Anxiety is directly related to a fear of gaining weight.Body weight <85% of ideal.
No differentiating tests exist.
Situational anxiety (non-pathological)
Anxiety can be avoided and is more controllable and less pervasive.Situational worries are less likely to be accompanied by physical symptoms. [1]Restlessness, fatigue, and other physical symptoms are rarely present.
No differentiating tests exist.
Adjustment disorder
Anxiety occurs temporarily in response to a life stressor and does not persist for more than 6 months after the stressor ends.
No differentiating tests exist.
Cardiac disease
Anxiety symptoms are predominantly cardiac in nature (i.e., palpitations, sensation of rapid heartbeat or skipped heartbeat, dizziness, dyspnoea on exertion, chest pain, and numbness).Chest pain is typically exertional.Cardiac risk factors may be present.Physical examination may be normal or show hypertension, hypotension, tachycardia or bradycardia, or S3 or S4 gallops.
Imaging studies such as angiogram, echocardiogram, exercise stress test, or ECG rule out cardiac disease.
Pulmonary conditions
There may be a history of pulmonary disease such as asthma or COPD, or signs/symptoms such as wheezing, cough, respiratory distress, or sputum production.Patients may specifically have a feeling of suffocation accompanied by physical signs.
Pulmonary function tests (or less commonly bronchoscopy) rule out primary lung pathology.Pulse oximetry shows low oxygen saturation.
Hyperthyroidism
Weight loss, warm moist skin, heat intolerance, ophthalmopathy, or goitre.
TFTs (increased T4, decreased TSH) can identify primary hyperthyroidism or use of excessive thyroid hormone.
Infections
Anxiety limited to the time period of the infection.Other symptoms include fever, night sweats, or cough.
Viral antibody titres, blood cultures, and acid-fast bacillus test of sputum can assess possible infectious causes.Successful treatment of infection should result in resolution of symptoms.
Peptic ulcer disease
Typically, burning epigastric pain which occurs hours after meals or with hunger, relieved by food or antacids.It may be difficult to distinguish gastrointestinal symptoms as a cause versus a result of anxiety.
Upper GI endoscopy detects peptic ulcer and possibly presence of Helicobacter pylori.
Crohn's disease
Chronic diarrhoea, weight loss, and right lower quadrant abdominal pain mimicking acute appendicitis.Perianal lesions including skin tags, fistulae, abscesses, scarring or sinuses.It may be difficult to distinguish gastrointestinal symptoms as a cause versus a result of anxiety.
Colonoscopy shows aphthous ulcers, hyperaemia, oedema, cobblestoning, or skip lesions.
Irritable bowel syndrome
Alteration of bowel habits associated with pain, and abdominal discomfort, bloating, or distention.It may be difficult to distinguish gastrointestinal symptoms as a cause versus a result of anxiety.
No differentiating tests. Diagnosis is clinical and investigations only performed to exclude other causes.

Generalised seizures

Psychogenic non-epileptic seizures
Patients with psychogenic non-epileptic seizures will often present with continuous limb shaking similar to generalised tonic-clonic seizures (GTCSs), but with suggestive elements: variable maintenance of consciousness, eye closure, side-to-side head shaking, pelvic thrusting, waxing/waning course, prolonged convulsive activity, lack of response to benzodiazepines.
Video-EEG monitoring is the definitive test to differentiate epileptic seizures from psychogenic non-epileptic seizures.In the emergency setting, a prolactin level can be used as well; patients with psychogenic non-epileptic seizures will have a normal value.
Convulsive syncope
Vasovagal syncope can often present with brief convulsive activity (<15 seconds) in the limbs shortly after loss of consciousness.A detailed history of the event itself is often useful and critical for the diagnosis; a typical syncope is often position-dependent and briefly preceded by a feeling of light-headedness. Further, the loss of consciousness is typically very brief, and there is a relatively quick return to baseline.
A tilt-table test can be utilised, but is a relatively non-specific assessment. Serum CK drawn serially can be used to differentiate from an epileptic seizure although it is not routinely used. [31] This is because although a high CK would be suggestive of an epileptic seizure, a normal CK does not exclude one as unconsciousness with prolonged immobility for any cause can result in a high CK. In this situation, an accurate clinical history is seen as more important than any test.
Cardiac arrhythmia
Primary cardiac arrhythmias often present with sudden loss of consciousness, sometimes preceded by a feeling of palpitations or sudden anxiety. Generally, arrhythmias occur abruptly and without the prolonged evolution of convulsions that are typical of a GTCS. Additionally, patients with arrhythmia often return to baseline relatively rapidly.
An ECG is indicated for any patient with a potential cardiac arrhythmia. For those patients with a normal ECG and a high index of suspicion, a Holter monitor is warranted.
Transient ischaemic attack (TIA)
In some cases, TIAs can present with either a sudden alteration in consciousness or focal motor movements (limb-shaking TIA). Although these are rarely confused with GTCSs, they must be considered.A thorough history and neurological examination are indicated to evaluate for TIA.
A non-contrast head CT or MRI can be used to assess vascular abnormalities that suggest a TIA. If available, an EEG can be used to evaluate for epileptiform activity.
Narcolepsy
Cataplexy presents with a sudden loss of tone during wakefulness and is sometimes included in the differential for seizures. This is rarely confused for a GTCS.
A polysomnogram and multiple sleep latency tests are utilised to diagnose narcolepsy with cataplexy.An EEG can also be used to evaluate for the possibility of epilepsy.

Generalised seizures in children

Pseudo-seizures
Characteristics of non-epileptic attacks help to differentiate them from epileptic seizures. [35] It is important to note that non-epileptic attacks often occur in children who are also experiencing true epileptic seizures.Can be provoked by emotional precipitants, do not occur while the patient is asleep and are intractable despite adequate medicine. Tend to occur in the presence of witnesses.Onset of the seizure is often gradual and injury during the fall at the start of the seizure is rare.No post-ictal phase or amnesia for the time surrounding the event. No pathological reflexes elicitable just after the seizure.Patient may have history of sexual or other abuse.
Normal EEG during the event.
Breath-holding spells (prolonged cyanotic expiratory apnoea)
Often precipitated by anger or frustration.Typically vigorous cry is followed by a period of blocked respiration resulting in cyanosis, loss of consciousness and sometimes opisthotonic posturing (i.e., muscle spasm leading to pronounced hyper-extension with head and lower limbs bent backwards and the trunk arched forwards).
ECG during the event may show initial tachycardia followed by bradycardia.
Long QT syndrome
Often positive family history.History of syncope triggered by pain, fear, or exercise.
ECG shows prolonged corrected QT interval.No epileptic discharges on EEG during the episode but, depending on the duration of asystole, hypoxic slowing of the EEG may be seen during the attack.
Syncope
Often happens in standing position and is accompanied by pallor and sweating.May be precipitated by painful stimuli.Usually quick recovery and no post-ictal phase.
Tilt-table testing can confirm a diagnosis of vasovagal syncope, the most common type.12-lead ECG is the only test needed and excludes prolonged QT syndrome.
Parasomnias
Occur mostly in the first few hours of sleep and usually not repetitive in same night.Sleep behaviours such as sleepwalking and eating while asleep may be present.
Normal EEG during the event.
Paroxysmal movement disorders
Includes tics, episodic ataxias, or paroxysmal dyskinesias.Occasionally characteristics of the movements (e.g., location, speed, frequency) are different from seizure.
Normal EEG during the event.
Gastro-oesophageal reflux
Characterised by infant gasping and becoming suddenly apnoeic and stiff.May be a change of skin colour.Infant may appear startled.Bizarre posturing that may accompany this event is known as Sandifer's syndrome.Usually occurs within 1 hour or so of a feed.
Trial of treatment with H2 antagonists, proton-pump inhibitors, or antacids terminates the events.
Inattention/daydreaming
Episodes can be interrupted and do not finish suddenly.Not accompanied by automatisms.
Inter-ictal and ictal EEG are normal.
Panic disorder
Attacks usually occur during periods of particular stress.May be accompanied by chest pain or paraesthesias.No post-ictal phase.
Normal EEG during the event.
Self-gratification behaviour
Infantile masturbation may be confused with seizure disorder.Rhythmic hip flexion and adduction accompanied by a distant expression.Period of sleepiness afterwards should not be confused with post-ictal phase.
Normal EEG during the event.
Reflex anoxic seizures
Also called reflex asystolic syncope.Usually precipitated by mild injury.Cerebral hypoxia may lead to opisthotonic posturing and brief clonic movements.No post-ictal phase.
An ECG during the event will document asystole.
Febrile seizures
Presence of fever.
Diagnosis is clinical.EEG is normal.

Genetic disorders of sexual development

Micropenis due to another cause
Isolated micropenis suggests inadequate testosterone production in the third trimester of gestation only.Most are due to hypogonadotropic hypogonadism (patients present with delayed puberty and no ambiguity of the genitals), growth hormone deficiency (short stature, poor growth), or as a part of a genetic syndrome (e.g., Prader-Willi syndrome).Patients typically have normal testes palpable, no hypospadias, and a normal 46,XY karyotype.
Clinical diagnosis.No hormonal testing required if an isolated abnormality.
Unilateral undescended testes (cryptorchidism)
Patients with isolated unilateral undescended testes have no micropenis, no hypospadias, and a normal 46,XY karyotype.Extremely common in normal boys, especially preterm infants.Bilateral abdominal testes are not common and further evaluation is indicated.
Clinical diagnosis.Ultrasound abdomen/pelvis may be used to locate the testes.No further hormonal evaluation is indicated if this is an isolated finding.

Genital tract chlamydia infection

Gonorrhoea infection
Signs and symptoms of cervical or male urethral discharge are generally more pronounced with gonorrhoea.
Nucleic acid amplification test (NAAT) test for gonorrhoea alone is positive. May see gram-negative intracellular diplococci on infected specimens.
Bacterial vaginosis
Discharge tends to be greenish-grey and have a fishy odour.
Clue cells will be present on microscopic examination.
Vaginal candidiasis
Discharge is thick and white in the vaginal vault. External genital symptoms such as itching and burning are more likely.
Hyphae or budding yeast present on microscopic examination of KOH (potassium hydroxide) preparation of vaginal secretions.
Trichomonas vaginitis
Men tend to be asymptomatic but can be carriers. Women usually have a thin, greyish, frothy vaginal discharge in the vaginal vault. Discharge tends to be worse straight after menses. The cervix may be inflamed and have a strawberry appearance.
Mobile trichomonads present on microscopic examination.
Mycoplasma infection
Caused by the organism Mycoplasma genitalium. Frequently asymptomatic; however, can cause bacterial vaginosis, cervicitis, and PID in women, and urethritis in men.
Nucleic acid amplification test (NAAT) test for Mycoplasma genitalium is positive.
Pelvic inflammatory disease (PID)
A wide range of bacterial infections, including chlamydia, can ascend the female reproductive tract, causing pelvic or abdominal pain, fevers, nausea/vomiting, dyspareunia, and intramenstrual bleeding. Diagnostic criteria for PID include cervical motion tenderness and/or adnexal tenderness. The diagnosis is presumed when chlamydial infection and cervical motion tenderness coexist.
There are no differentiating tests. PID is a clinical diagnosis.

Genital warts

Condylomalata
One of the manifestations of secondary syphilis.Patients may have associated systemic signs and symptoms, such as fever, malaise, adenopathy, and weight loss.The lesions appear as moist, whitish, wart-like papules, and are highly contagious.View imageLesions relapse in approximately 20% of patients without treatment within a year. [3] [36]
Direct detection of treponemes in specimen under dark-field microscopy is diagnostic.Serological tests for syphilis, such as rapid plasma reagin (RPR), may be helpful.
Molluscum contagiosum
A viral infection of the epidermis that manifests as flesh-coloured papules that are often umbilicated.View imageThe infection is self-limited and lesions persist for up to 6 months.Occurs in children and sexually active adults. In children, the lesions are seen on exposed skin, but in sexually active adults, lesions occur in the genital region.In HIV-positive patients, the clinical presentation is generally more severe with a greater number of lesions and larger lesions that may involve the face.These lesions are usually asymptomatic unless secondarily infected, in which case they may be painful. [3] [37]
Diagnosis is usually clinical. However, direct microscopic examination of Giemsa-stained central core shows molluscum or inclusion bodies.Biopsy may be indicated in HIV-infected patients to rule out fungal infection.
Pearly penile papules
Pearly penile papules are a normal anatomic variant of the glans that appear as flesh-coloured, discrete papules approximately 1 to 2 mm in size, distributed evenly around the corona.They are asymptomatic but may generate anxiety in the patient. [3] [37]
Diagnosis is clinical.
Hidradenoma papilliferum
Smooth dermal or subcutaneous nodule, usually 1 cm or less in diameter. [38]
Biopsy showing a pronounced papillary pattern with apocrine epithelium lining the constituent papillae. [38]
Seborrhoeic keratosis
Common, benign verrucous lesions that may vary in colour from tan to brown to gray to black. They have a classic 'stuck-on' appearance.View imageThey evolve over months to years and rarely occur before the age of 30. [3] [37]The lesions tend to appear on the face, torso, and upper extremities.
Diagnosis is clinical.
Carcinoma in sit
May appear as multifocal erythematous macules, lichenoid, or pigmented papules sometimes forming plaques on the external anogenital region. The surface is usually smooth and velvety.Ulceration suggests invasiveness. Cervix and anus involvement have the highest risk to become invasive.
Diagnosis is clinical; however, it should always be confirmed by biopsy.Dermatopathology shows epidermal proliferation with numerous abnormal mitoses, dyskeratotic cells, and atypical pleomorphic cells with large hyperchromatic nuclei. [37]
Bowenoid papulosis/erythroplasia of Queyrat
Bowenoid papulosis can appear as red-brown papules that may coalesce to form a plaque. These can often closely resemble benign condylomata.Erythroplasia of Queyrat typically appears as a erythematous, well-defined, velvety plaque of the glans or vulva. [5]
Atypical proliferating suprabasal cells present in the full thickness of the epithelium. [37]
Skin tags
Soft, skin-coloured or tan-brown, round-oval, pedunculated papilloma.Normally constricted at the base, and the size varies from 1 mm to 1 cm.
Diagnosis is clinical. [37]

Gestational diabetes

type 1 diabetes
There may be no difference in signs and symptoms, although glucose level deterioration and tendency for ketosis is generally greater. [1] Women with type 1 diabetes are more likely to be white and lean.Clinical evidence of diabetic complications, such as neuropathy, retinopathy, and albuminuria, would indicate longer-standing hyperglycaemia that antedated pregnancy.[C Evidence]
Anti-beta cell serologies (e.g., glutamic acid decarboxylase-65 [GAD-65] and anti-insulin antibodies) and postpartum glycaemia testing can be performed. [1]The finding of a markedly elevated HbA1c level or fasting plasma glucose, especially early in pregnancy, suggests that diabetes existed before pregnancy.
type 2 diabetes
There may be no difference in signs and symptoms in women with GDM who had unrecognised type 2 diabetes before pregnancy.Compared with women with autoimmune (type 1) diabetes, women with type 2 diabetes are more likely to be obese, have a family history of type 2 diabetes, and exhibit evidence of insulin resistance, such as dyslipidaemia, acanthosis nigricans, or history suggesting polycystic ovarian syndrome.Clinical evidence of diabetic complications, such as neuropathy, retinopathy, and albuminuria, would indicate longer-standing hyperglycaemia that antedated pregnancy.[C Evidence]
The finding of a markedly elevated HbA1c level or fasting plasma glucose, especially early in pregnancy, suggests that diabetes existed before pregnancy. [1]

Gestational hypertension

Pre-eclampsia
Greater than expected weight gain, peripheral oedema, blurred vision, and headaches.
Proteinuria is ≥300 mg/L in 24 hours, or dipstick is persistently ≥1 g/L.
Eclampsia
Eclampsia is pre-eclampsia superimposed with seizures and convulsions during the ante-, intra-, or postpartum period.
Proteinuria is ≥300 mg/L in 24 hours, or dipstick is persistently ≥1 g/L.
Hypertension, essential
The woman already has an established history of hypertension prior to pregnancy, or hypertension persists after 12 weeks postpartum.
Clinical diagnosis.

Giant cell arteritis

Polymyalgia rheumatica (PMR)
Typical symptoms of PMR include aching and stiffness in the shoulders and proximal limb muscles, with or without mild polyarthritis or tenosynovitis. Although GCA and PMR frequently co-exist, cranial symptoms including headache, jaw claudication, and vision symptoms are typically absent in patients with PMR. PMR typically has less prominent symptoms than GCA.
No specific diagnostic tests, but diagnosis is supported by history, physical examination, and raised inflammatory markers (ESR >40 mm/hour). A rapid response to oral corticosteroids makes the diagnosis more likely.
Solid organ cancers and haematological malignancies
Clinical presentation may be similar in solid-organ cancers and haematological malignancies, especially multiple myeloma and lymphoma.
A thorough physical examination, including careful breast exam should be performed as well as age-appropriate cancer screening studies (e.g., mammogram). Haematological studies including protein electrophoresis, lymphocyte immunophenotyping, and bone marrow biopsy may reveal evidence of multiple myeloma. CXR and CT may reveal enlarged nodes in lymphoma.
Takayas's arteritis (TA)
The major factors differentiating TA from GCA are age at disease onset and lack of involvement of cranial arteries. Typically occurs in young women, usually in their 20s and 30s. Although systemic symptoms are also common in TA, cranial symptoms are usually absent. Patients with TA often have absent or asymmetric peripheral pulses and multiple arterial bruits.Occasional mild, chronic TA may not be diagnosed until after the patient is 50 years old. They may have had longstanding symptoms of decreased aortic or aortic branch outflow, such as dizzy spells, or been noted as having an unexplained lack of a pulse in one arm.
Aortic arch or other targeted angiography, CT, or magnetic resonance angiography.
Chronic infection
There may not be any differentiating signs or symptoms.
Investigations depend on the infection being considered. These include multiple blood cultures and echocardiography for infective endocarditis, CXR and sputum culture for TB, and serological tests for other chronic infections including hepatitis B and C.
Rheumatoid arthritis
Symmetric small joint polyarthritis and extra-articular manifestations are characteristic of rheumatoid arthritis and distinguish this condition from GCA.
May have positive RF and anticyclic citrullinated peptide antibodies. May have radiographic, ultrasound, or MRI evidence of joint erosions.
Amyloidosis
Amyloidosis can rarely cause jaw and tongue claudication, although these are very characteristic of GCA. [25]
Serum immunoelectrophoresis may show a monoclonal band. Amyloidosis is distinguishable from GCA by lack of response to therapy and by staining of a temporal artery specimen for amyloid. Rectal or abdominal fat biopsy and serum amyloid P scan may be positive.
Non-arteritic anterior ischaemic optic neuropathy (NAION)
Symptoms may mimic GCA. The presence of other symptoms (e.g., PMR, headache, and jaw claudication) in the presence of elevated levels of inflammatory markers clearly distinguishes GCA from NAION.
There are no specific differentiating tests.
SLE
Distinguishing features are the presence of photosensitivity, skin rash, oral ulcers, and symptoms of pleuropericarditis.
May see positive ANA, antibody to double-stranded DNA, or antibodies to extractable nuclear antigens. Laboratory evidence of cytopenias or glomerulonephritis.
Overlap connective tissue disease
Distinguishing features are the presence of photosensitivity, skin rash, oral ulcers, and symptoms of pleuropericarditis.
May see positive ANA, antibody to double-stranded DNA, or antibodies to extractable nuclear antigens. Laboratory evidence of cytopenias or glomerulonephritis.
Hypothyroidism
Myalgias due to hypothyroidism should respond promptly to thyroid replacement therapy; cranial symptoms are absent.
Thyroid function tests may reveal low T4.
Polymyositis
Proximal muscle weakness is the predominant symptom.
Elevated levels of muscle enzymes and abnormalities on EMG.
Breast carcinoma
Nodules or pain in the breast, with or without tenderness; significant constitutional symptoms may be present.
Biopsy is indispensable for establishing a definitive diagnosis.

Giardiasis

Rotavirus gastroenteritis
Common in children between the ages of 6 months and 2 years.Results in severe dehydration and even death.The incubation period for rotavirus disease is approximately 2 days. The disease is characterised by vomiting and watery diarrhoea for 3-8 days, and fever and abdominal pain occur frequently. [57]Affected children are frequently simultaneously infected with both respiratory and GI viruses, making interpretation of these findings more difficult.
ELISA and latex agglutination test on stool samples will be positive for rotavirus.
Functional diarrhoea
Defined as loose (mush) or watery stools without pain occurring in at least 75% of stools for a period of at least 3 months with symptom onset at least 6 months before diagnosis.Does not result in weight loss.
This is a diagnosis of exclusion and has no definitive investigation.
Gluten enteropathy
Autoimmune process resulting from an inappropriate immune response to the dietary protein gluten.Wide range of symptoms, including gas, recurring abdominal bloating and pain, chronic diarrhoea or constipation; pale, foul-smelling or fatty stool, weight loss/weight gain, fatigue, unexplained anaemia, behavioural changes, irritability common in children; tingling numbness in the legs (from nerve damage); bone or joint pain, muscle cramps; delayed growth in children or failure to thrive in infants; aphthous ulcers, dermatitis herpetiformis, osteoporosis (especially at a young age), iron deficiency. [58]
Test for serum immunoglobulin A (IgA) tissue transglutaminase (tTG) antibodies. A positive IgA tTG result should prompt small bowel biopsy with at least 4 tissue samples to confirm the diagnosis.Adherence to a gluten-free diet may eliminate symptoms within a few months. [58]
Ulcerative colitis
Onset between ages 15 and 40.Almost always involves the rectum and may extend in a proximal and continuous fashion to involve other portions of the colon. Symptoms vary from intermittent rectal bleeding associated with the passage of mucus to frequent loose, bloody stools.
Colonoscopy and biopsy: vascular markings are lost due to engorgement of the mucosa, giving it an erythematous appearance. In addition, petechiae, exudates, touch friability, and frank haemorrhage may be present. Colonic involvement is continuous. More severe cases may be associated with macroulcerations, profuse bleeding, and copious exudates.
Crohn's disease
Onset between ages 15 and 40.May involve the entire GI tract from mouth to perianal area. Fatigue, prolonged diarrhoea with abdominal pain, weight loss, and fever, with or without gross bleeding, are the hallmarks of Crohn's disease.Although Hemoccult-positive stools are common in Crohn's disease, gross bleeding is much less frequent.
Colonoscopy and biopsy: focal ulcerations adjacent to areas of normal-appearing mucosa along with polypoid mucosal changes that give a cobblestone appearance. Skip areas of involvement are typical with segments of normal-appearing bowel interrupted by large areas of obvious disease; this pattern is different from the continuous involvement in ulcerative colitis. Pseudopolyps are also often present.
Microscopic colitis
Usually middle-aged patients presenting with chronic watery diarrhoea without bleeding.
Colonoscopy and biopsy: diagnosis is made on histology. Classically characterised by colonic mucosal subepithelial collagen deposition with intra-epithelial lymphocytic infiltration.
Infectious diarrhoea
Specific risk factors such as travel, HIV infection, use of antibiotics, and consumption of potentially contaminated drinking water.
Stool for ova/parasites, Clostridium difficile toxin, modified acid-fast stains, and culture.
Irritable bowel syndrome (IBS)
IBS is a GI syndrome characterised by chronic abdominal pain and altered bowel habits in the absence of any organic cause. Younger patients and women are more likely to be diagnosed with IBS.Does not result in weight loss.
Symptom-based criteria. Diagnosis of exclusion.

Gilbert's syndrome

Haemolysis
Signs and symptoms of anaemia (fatigue, dizziness, dyspnoea, pallor, tachycardia). Splenomegaly may be present in some causes of haemolysis (hereditary spherocytosis, non-Hodgkin's lymphoma, or portal hypertension due to cirrhosis). However, up to 60% of patients with Gilbert's syndrome in some series demonstrate a mild haemolytic picture. In addition, Gilbert's syndrome may coexist with hereditary haemolytic anaemias.
FBC: abnormalPeripheral smear: abnormalReticulocyte count: abnormalLactate dehydrogenase: elevated (normal in Gilbert's syndrome)
Acute and chronic liver disease
Patients with liver disease often have hepatomegaly, splenomegaly, spider angiomas, palmar erythaema, encephalopathy, and gynaecomastia.
Ultrasound: may show hepatomegaly, splenomegaly, and sluggish or retrograde portal vein flowFBC: thrombocytopenia and anaemiaClotting profile: coagulopathyLiver aminotransferases: elevatedAlkaline phosphatase: elevatedGamma-glutamyltransferase (GGT): elevated
Cardiac disease (e.g., congenital heart disease and valvular heart disease)
Clubbing, heart murmur, shortness of breath, palpitations, orthopnoea, paroxysmal nocturnal dyspnoea.
Echocardiogram: abnormalAbdominal ultrasound: dilated inferior vena cava and hepatic and portal vesselsLiver aminotransferases: elevated
Biliary tract disease
Pruritus, acholic stools, bilirubinuria.
Imaging: abnormal bile ductsAlkaline phosphatase: elevatedGGT: elevatedLiver aminotransferases: elevated
Thyrotoxicosis
Tremor, palpitations, tachycardia, diaphoresis, diarrhoea.
TSH: decreasedSerum-free T4: elevatedSerum-free T3: elevated
Rhabdomyolysis
Myalgia, arthralgia, weakness.
Creatine phosphokinase: elevatedUrea and creatinine: possibly elevated
Crigler-Najjar syndrome type I
Kernicterus or neurological deficits.
Bilirubin level: usually >342 micromol/L (>20 mg/dL)
Crigler-Najjar syndrome type II
Bilirubin encephalopathy, though rare, can be induced by factors such as infection or anaesthesia.
Bilirubin level: generally between 102 and 427 micromol/L (6 and 25 mg/dL)
Medication-induced hyperbilirubinaemia
Numerous (e.g., oedema, ataxia, nausea, vomiting).
Liver aminotransferase: usually elevated with medicines such as rifamycin or probenecid. Abnormalities should improve after withdrawal of offending agent.

Gingivitis

Oral lichen planus
A chronic inflammatory mucocutaneous disease which commonly manifests on the gingiva and is characterised by red, non-swollen gingivae with painful atrophic/ulcerative lesions. White papular, reticular, and plaque-type lesions, usually asymptomatic, may also be found as the only sign of gingival involvement or occur at the periphery of the atrophic lesions. It is generally nonresponsive to routine oral hygiene procedures. It may also develop on oral mucosa (50%-70% of cases), other mucosal surfaces and on skin of extremities. [30] Oral lesions may occur in the absence of skin lesions.View imageView image
Direct immunofluorescence is negative for all auto-antibodies but positive for fibrinogen fluorescence outlining the basement membrane zone with irregular extensions into the superficial lamina propria (shaggy appearance). [31]Histopathology reveals a dense lymphocytic infiltrate with possible possible changes to the epithelium.
Pemphigoid
A group of chronic, mucocutaneous autoimmune disorders in which autoantibodies are directed towards components of the basement membrane and characterised by bullae and blisters that rupture leaving superficial, painful, persistent ulcerations. The average age of onset is 50 to 60 years. Since healing may occassionally leave scars, ocular involvement may lead to conjunctival scarring and blindness. The oral lesions usually do not result in scarring. If only mucous membranes are affected, the term mucous membrane pemphigoid (MMP) is used. [32] Gingival involvement is characterised by the clinical pattern known as desquamative gingivitis or by localised bullous formation quickly evolving into painful and persisting erosions. [30] View image
Linear band of IgG, C3, and sometimes other immunoglobulins as well as fibrin at the basement membrane zone. [33] [34]Indirect immunofluorescence (IIF) is negative, but salt-split-skin IIF is positive in up to 50% of the cases. [35]
Pemphigus
A group of autoimmune diseases characterised by formation of intraepithelial bullae in skin and mucous membranes. The average age of onset is 50 years and it is rarely seen in children. A positive Nikolsky sign is seen (top layers of skin slide over lower layers when rubbed). The typical oral lesions are chronic, superficial, ragged, irregular, painful erosions. Gingival involvement usually appears in the form of desquamative gingivitis. Since the bulla formation is located in the spinous cell layer, the chance of finding an intact bulla on the oral mucosa is quite small. Lesions may develop on mucosal surfaces earlier than they develop on the skin, although skin lesions are more common. Conjunctival involvement is uncommon and, unlike pemphigoid, the ocular lesions of pemphigus do not produce scarring. [32] View image
Direct immunofluorescence is positive for intercellular IgG and C3 between epithelial cells; no linear reactivity along basement membrane zone. IIF is positive. [33] [34]
Lupus erythematosus
Oral mucosal lesions resemble erosive lichen planus with erosions and striae but also demonstrate atrophy with fine white stippling not seen in erosive lichen planus. [32] Systemic lupus erythematosus may also give rise to gingival ulceration and increased plaque-related gingivitis secondary to Sjogren's syndrome.View image Can give rise to desquamative gingivitis.
Direct immunofluorescence is positive for IgM, IgG, and/or C3 in a shaggy or granular band at the basement membrane zone. [36] Serum ANAs and antidouble-stranded DNA usually occur in SLE.
Desquamative gingivitis
A clinical reaction pattern produced by several disorders that involve the gingiva. This pattern is characterised by an extensive desquamation and/or erosion of the affected gingival, particularly in the buccal aspect of anterior teeth. Often marginal gingival is unaffected in the absence of plaque accumulation. [32]
Biopsy reveals in about 80% of cases features that are diagnostic of mucous membrane pemphigoid and oral lichen planus. Less frequently biopsy shows features that are diagnostic of pemphigus vulgaris, linear IgA disease, epidermolysis bullosa acquisita, systemic lupus erythematosus, chronic ulcerative stomatitis, and paraneoplastic pemphigus. [37]
Drug-associated gingival enlargement
Patients have a 1- to 3-month minimum history of therapy with phenytoin, cyclosporine, or calcium-channel blockers such as nifedipine and less commonly amlodipine, verapamil, felodipine, and diltiazem. [38] Gingiva is often of normal colour with enlargement ranging from focal to extensive enlargement that covers most of the teeth and may impair mastication of food. In the presence of secondary inflammation caused by dental plaque, the gingiva may be reddened, puffy, and painful.View imageView image
Diagnosis is by clinical oral exam and review of medical history. Treatment options are usually oral hygiene maintenance, gingival surgery and rarely substituting an acceptable alternative drug.
Primary herpetic gingivostomatitis
Primary herpetic gingivostomatitis has a bimodal age distribution of 2 to 3 years and >60 years. [32] Clusters of small vesicles coalesce to form blisters that rupture to leave painful mucosal ulcerations. The gingivae are enlarged, very erythematous, and painful. The gingival features can be in a form similar to necrotising ulcerative gingivitis, but gingival lesions are less severe and without significant haemorrhage. More significantly, other mucosal surfaces are likely involved with clusters of painful ruptured vesicles.View image Affected patients may be febrile, have cervical lymphadenopathy and occassionally skin rashes.
No specific tests are needed. Cytological smear may confirm viral inclusions. The disease is self-limiting, lasting up to 2 weeks in immunocompetent patients. Recurrence suggests immunodeficiency.
Allergic reactions
Allergic reactions occasionally occur after the use of mouthwashes, toothpastes, or chewing gums. The allergens responsible for such reactions may be flavour additives (e.g., cinammon) or preservatives, or may be contained in materials or drugs used by dentists or in foods, natural products, or lipsticks. [30] Clinically, the allergic reaction appears as a swollen red area, sometimes with painful ulcerations or white striae. This disorder can affect other mucosal surfaces where the allergen makes contact. Plasma cell gingivitis is a distinctive form of allergic reaction characterised by a dense inflammatory infiltrate consisting predominantly of plasma cells. [32] View image
Withdrawal of suspected offending agent brings relief within 1 week. [39] [40]Patch testing may be useful. [41]
Leukaemia
Leukemia presents in the oral cavity with spontaneous hemorrhage, petechiae and possible pain. [32] Gingival enlargement is most likely with acute myeloid leukaemia. Ulcers may be present on the gingival and the mucosal surfaces. Gingival manifestations are more common in acute than chronic leukaemia. View image
Full blood count and blood film will usually establish the leukaemic type.
Primary and metastatic carcinoma
Most gingival carcinomas, both primary and metastatic, present with localised exophytic masses rather than diffuse pseudo-inflammatory changes generally associated with gingivitis.View imageView image
Radiology and biopsy. Primary gingival carcinoma usually shows squamous epithelial carcinoma; findings for metastatic disease are indicative of the primary carcinoma.
HIV linear gingivitis
HIV linear gingivitis is characterised by a distinct 2- to 3-mm linear band of pronounced erythema along the gingival margin directly adjacent to the teeth that does not respond to conventional oral hygiene procedures. [32]
No specific diagnostic test. Non-response to standard therapy is suggestive. Confirm HIV status. Some cases are associated with candidiasis.
Foreign body gingivitis
Gingival inflammation associated with foreign bodies located in the connective tissue deep to the sulcular epithelium. It often presents as a red or combined red-white lesion frequently misdiagnosed as oral lichen planus. Pain or sensitivity is a common finding and the lesion does not resolve with optimisation of oral hygiene. Foreign bodies can originate from a wide variety of dental materials. [32]
Diagnosis is from history and clinical features.Biopsy demonstrates a non-specific pattern of chronic or subacute mucositis and a foreign body (but in some cases the foreign material may be too fine to be detected).When granulomatous inflammation is microscopically found (approximately 20% of cases) and a foreign body is not detected, the clinician must search for signs and symptoms of granulomatous diseases (Crohn’s disease, sarcoidosis, tuberculosis, orofacial granulomatosis). [32]
Orofacial granulomatosis
An idiopathic disorder due to an abnormal immune reaction. Lips are frequently affected and show a non-tender, persistent enlargement. The tongue may develop fissures, oedema, erosions, paraesthesia, and taste alteration. Gingival lesions present as swelling and slight eythema mimicking plaque-related gingivitis, or as painful erosions. [30]
Biopsy reveals a non-specific granulomatous inflammation associated with negative stains for organisms and no foreign body. Local and systemic granulomatous diseases must be considered in the differential diagnosis.
Pyostomatitis vegetans
A relatively rare, pustular disorder of the oral mucosa associated with inflammatory bowel diseases, particularly ulcerative colitis or Crohn’s disease. The typical lesions of this disorder are multiple, painless, yellow-white, vegetative mucosal folds and microabscesses, which may be present on both gingival and oral mucosa. [32]
Biopsy reveals an acantholytic appearance of the epithelium due to the presence of numerous eosinophils, often forming intraepithelial microabscesses.Direct immunofluorescence rules out chronic bullous oral diseases.
Linear IgA disease
Oral lesions present as desquamative gingivitis alone or in association with vesicles, painful erosions, and ulceration. [42] Lesions affect the hard and soft palates, tonsillar pillars, buccal mucosa, tongue, and gingiva. Oral lesions occur always in the presence of skin lesions. [43]
Direct immunofluorescence is characterised by linear deposition of IgA along the dermoepidermal basement membrane zone. [32] Circulating antibasement membrane IgA may be detected using IIF in approximately 30% of patients.Exclusive oral lesions showing linear IgA staining at the basement membrane zone should be considered mucous membrane pemphigoid not linear IgA disease. [44]
Wegener's granulomatosis
Oral involvement is rare. [32] When present, it is considered an early sign of disease. Characteristic lesions include dramatic gingival hyperplasia with short bulbous, friable, and haemorrhagic projections beginning in the interdental papillae, commonly referred to as 'strawberry gingivitis'. The upper gingivae are the most commonly affected site in the mouth.
Biopsy shows leukocytoclastic vasculitis. [45] In oral biopsies, due to the paucity of large vessels, vasculitis may be difficult to demonstrate. Gingival biopsy specimens usually show prominent vascularity with extensive red blood cell extravasation. [32]Circulating perinuclear antineutrophil cytoplasm (p-ANCA) or cytoplasmic antineutrophil cytoplasm (c-ANCA) antibody may be detected.Indirect immunofluorescence (IIF) is positive for cytoplasmic antineutrophil cytoplasm antibody (c-ANCA). A positive reaction for proteinase 3, the major antigen for c-ANCA that resides in the azurophilic granules of neutrophils, is needed to confirm the positive IIF for c-ANCA. [46]
Erythema multiforme
Acute onset of symmetrically distributed cutaneous target lesions often accompanied by mucous membrane involvement. [32] Gingival involvement is extremely rare but may give rise to desquamative gingivitis and/or gingival ulceration. Patients may have a recent history of HSV infection, mycoplasma infection, drug therapy (e.g., anticonvulsives and antibiotics) or immunisation.View image
Histopathology is rarely helpful as the features are usually non-specific. Hence diagnosis is based on clinical features and exclusion of other vesiculo-erosive disorders. [47]
Agranulocytosis
Gingiva appears as necrotising ulcerative gingivitis, but patient has a history of exposure to drugs that cause decreased granulocyte production, such as anticancer chemotherapeutic agents, or a history of congenital disease associated with decreased levels of granulocyte-specific colony-stimulating factor (G-CSF). Malaise, fever, pharyngitis, and painful stomatitis may accompany necrotic, punched-out ulcerations of multiple mucosal surfaces.
Discontinuation of the suspect drug leading to resolution within 2 weeks may be diagnostic.FBC shows granulocytopenia (<0.5 X10^9/L or <500 cells/mm^3) and normal erythrocytes and platelets. [32]
Histoplasmosis
Very rare. Oral lesions may occur with disseminated form of the disease in older or immunocompromised patients. [32] They appear as chronic ulcers with firm rolled margins and may resemble oral carcinoma of the gingiva.
Biopsy reveals granulomatous inflammation with periodic acid-Schiff and Gomori methenamine silver-positive fungi, morphologically consistent with Histoplasma capsulatum infection. [48]Non-culture methods include zymogen-based colorimetric assays to detect (13)-beta-D-glucan and molecular methods to detect fungal DNA.
Cyclic neutropenia
Cyclic neutropenia is a rare haematological disorder seen in children as a uniformly episodic fever, cervical lymphadenopathy, pharyngitis, and mucosal ulcerations that are most severe in the gingiva. [32] The average cycle length is 21 ± 3 days, with a range of 14 to 40 days. Alveolar bone loss (from maxillary or mandibular bones) and tooth mobility may develop.
Sequential FBCs show neutrophil counts <0.5 X10^9/L (500/mm^3 or 500/microlitre) for 3 to 5 days during 3 successive cycles. [32]

Glomerulonephritis

Nephrolithiasis
Patients usually have severe pain in addition to haematuria. The site and radiation of pain depend on the position of the stone.
Urinalysis shows haematuria, but no dysmorphic RBCs or casts. IV pyelogram or renal ultrasound reveals the stone.
Bladder cancer
Important cause of painless haematuria. Patients are older and mostly have a history of smoking.
Urinalysis shows haematuria, but no dysmorphic RBCs or casts. Diagnosis is made by cystoscopy and biopsy of the lesion.
Renal cancer
A triad of flank pain, fever, and haematuria is typical. Many cases are detected incidentally when a CT is done for other purposes.
Urinalysis shows haematuria, but no dysmorphic RBCs or casts. Imaging by CT would reveal a renal mass.
Pre- or post-renal failure
Patients present with vague generalised symptoms (fatigue, loss of appetite, and nausea) besides those of the underlying aetiology.
Urinalysis does not reveal dysmorphic RBCs or casts. Fractional excretion of sodium is <1% in azotaemia (abnormal levels of nitrogen-containing compounds in the blood) due to pre-renal causes.Renal imaging (ultrasound or CT) shows obstructive uropathy.

Glucose-6-phosphate dehydrogenase deficiency

Sickle cell disease
History of intermittent painful crises.May have skin/cardiac/pulmonary/skeletal manifestations.
Blood film shows presence of nucleated RBCs, sickle-shaped cells, and Howell-Jolly bodies.High-performance liquid chromatography (HPLC) shows abnormal sickle cell haemoglobin (Hb S).Haemoglobin electrophoresis shows Hb S present in sickle cell disease.
Autoimmune haemolytic anaemia
History of precipitant, for example, causal drug, infection.May have associated connective tissue disease, splenomegaly.
Blood film shows presence of spherocytes, elliptocytes, and schistocytes.Direct antiglobulin test is positive.
Isoimmune haemolytic anaemia, for example, ABO incompatibility
Mother typically blood group O.Infant typically group A or B.
Blood film shows presence of spherocytes, elliptocytes, and schistocytes.Direct antiglobulin test is positive.
Unstable haemoglobin
Rare.No history of precipitant.
Blood film may show Heinz bodies.Screening tests for unstable haemoglobin positive.HPLC and haemoglobin electrophoresis demonstrate abnormal haemoglobin.
Methaemoglobinaemia
Rare.May be precipitated by oxidant drugs.
G6PD fluorescent tests and assay normal.Methaemoglobin reductase deficient.

Gonorrhoea infection

Chlamydia infection
There are no history or physical examination features that can distinguish between these organisms except for disseminated infection, which is unique to gonorrhoea.Chlamydia is around 10 times more common than gonorrhoea in young populations. [4] [25] Chlamydia does not seem to be efficient at colonising the pharynx and is less likely to be found there. In men having sex with men, Chlamydia is the most common cause of rectal infections. [45]A specific form of genital ulcers and proctitis (lymphogranuloma venereum or LGV) is also caused by Chlamydia from a less common strain of C trachomatis.
The absence of diplococcus on microscopic examination with sufficient WBC for a diagnosis of urethritis is suggestive of Chlamydia. Commercial nucleic acid amplification test (NAAT) is usually a coupled test combining both gonorrhoea and Chlamydia, therefore an ideal way to give a definite pathogenic diagnosis.Diagnosis of Chlamydia of the pharynx or rectum is by culture or with NAAT if available.Diagnosis of LGV is suggested from high titres of chlamydial antibodies, NAAT positive for Chlamydia, and the typical clinical presentation.
Trichomonas
Trichomonas vaginalis is a common STD and is generally under-reported. A recent survey of young Americans found an overall prevalence of 2.3%. [43] Common symptoms (e.g., vaginal discharge and itching) are not sufficient to distinguish gonorrhoea from trichomonas.T vaginalis is often diagnosed after failure of treatment for urethritis, in cases with negative tests for gonorrhoea and Chlamydia.
T vaginalis can be diagnosed by wet preparation from vaginal or urethral discharge but this technique has low sensitivity. Culture is the most efficacious test, but newer NAATs are becoming available and will allow more rapid diagnosis.
Other infectious causes of urethritis, cervicitis, PID, and epididymitis
Other microorganisms, which are sexually transmitted but not easily diagnosed, may cause both cervicitis and urethritis. These include atypical herpes simplex recurrences, Mycoplasma genitalium, and Ureaplasma urealyticum.PID may also be caused by a mixture of organisms.Epididymitis may be caused by enteric gram-negative organism, especially with a history of insertive anal sex or in older men (>35 years). [2]There are no specific differentiating features between these other infectious agents and gonorrhoea.
No commercial tests are available for M genitalium or U urealyticum.Suggestive symptoms with a positive antibody test to HSV-2 and repeated negative test results for other aetiologies suggest HSV infection.Urinary culture of gram-negative organisms may be positive in cases of epididymitis.
Candidal vaginitis or bacterial vaginosis
Does not usually involve the upper genital tract and is caused by yeast species or a disruption in normal bacterial flora (bacterial vaginosis). These types of vaginitis are not sexually transmitted.Presents as vaginal discharge, odour, and irritation.
Wet mount microscopic examination, cultures, or smears may show Candida.In bacterial vaginosis, clue cells may be seen on wet mount and amine whiff test may be positive.
Urinary tract infection, female
Common. Symptoms include dysuria, haematuria, and urgency. Left untreated the ascending infection may result in pyelonephritis with flank pain and fever.
Mid-stream urine culture positive for causative infectious agent.
Urinary tract infection, male
Symptoms include dysuria, haematuria, and urgency. Left untreated the ascending infection may result in pyelonephritis with flank pain and fever.
Mid-stream urine culture positive for causative infectious agent.

Goodpasture's syndrome

SLE
May have a history of lupus. Lupus is more common in black females and Goodpasture's syndrome is more common in white males. History and physical examination findings that could suggest lupus include rash, photosensitivity, hair loss, oral ulcers, and arthritis.
In lupus nephritis, ANA and anti-double stranded DNA are often elevated, and C3 and C4 often suppressed. [14] Renal biopsy shows immune complex deposition in a granular pattern.
Granulomatosis with polyangiitis (Wegener's)
Typically have upper airway symptoms, such as a history of sinusitis or chronic cough.
Anti-neutrophil cytoplasmic antibody (ANCA) is elevated in granulomatosis with polyangiitis but can also be positive in anti-glomerular basement membrane (anti-GBM) disease. Renal biopsy shows no immune complex deposition. [5]
Microscopic polyangiitis
None.
ANCA is elevated in microscopic polyangiitis but can also be positive in anti-glomerular basement membrane (anti-GBM) disease. Renal biopsy shows no immune complex deposition. [5]
Churg-Strauss syndrome
Typically have a history of asthma and atopic or allergic symptoms.
ANCA is elevated in Churg-Strauss syndrome, but can also be positive in anti-glomerular basement membrane (anti-GBM) disease. Renal biopsy shows no immune complex deposition. [5]
Glomerulonephritis (post-streptococcal)
Presents with only glomerulonephritis. Not a cause of pulmonary renal syndrome.
Anti-streptolysin O is typically elevated. C3 is typically depressed. Renal biopsy shows immune complex deposition in a granular pattern.
Bacterial endocarditis with associated immune complex glomerulonephritis
May have fevers, chills, and a heart murmur.
Positive blood cultures and vegetations seen on echocardiography are diagnostic of endocarditis. Renal biopsy will show immune complex deposition. [5]
Cryoglobulinaemia
May have hepatitis C, lymphoproliferative disorder, underlying autoimmune disease. Symptoms may include arthralgia, cutaneous vasculitis lesions.
Positive cryoglobulins.
Hepatitis B
May have jaundice, history of exposure.
Positive hepatitis serologies, abnormal LFTs.
Hepatitis C
May have jaundice, history of exposure.
Positive hepatitis serologies, abnormal LFTs.

Gout

Pseudogout (calcium pyrophosphate deposition disease)
Presentation may be identical to that of gout.Is less common in people younger than 50 years of age.Is more likely to affect wrist and knee joints.
Chondrocalcinosis (radiographic calcification of cartilage in certain joints) is usually present.The definitive diagnosis is finding calcium pyrophosphate crystals in the synovial fluid. These are rhomboid-shaped, weakly positively birefringent crystals.
Septic arthritis
Presentation may be identical to that of gout.Occurs in both sexes and at any age.Risk factors for infection, such as intravenous drug use and immunocompromise, may be present.
Synovial fluid microscopy and culture may be Gram positive and show growth.Blood cultures may grow the causal bacteria.Co-existence of crystals and infection in the joint is not uncommon.
Trauma
A positive history is present.Usually, there are fewer inflammatory signs, such as erythema or warmth, on joint examination than with gout.
Synovial fluid is usually bloody and has no monosodium urate crystals.
Rheumatoid arthritis (RA)
Chronic tophaceous and polyarticular gout may present like RA, and tophi can be misdiagnosed as rheumatoid nodules.History of intermittent, acute, self-limited attacks of arthritis and podagra suggests gout.RA and gout appear to be negatively correlated, as very few cases of co-existence have been reported.
Associated with positive RF in 70% to 78% of cases; however, 30% of patients with gout have a positive RF. [44]Anticyclic citrullinated peptide (anti-CCP) is a new diagnostic test for RA. It has a high specificity, but a low sensitivity and it may be useful in the early detection of patients who will have severe RA. [45]Synovial fluid is inflammatory (WCC count >2.0 x 10^9/L or 2000/mm^3 or 2000/microlitre), but no monosodium urate crystals are found.
Reactive arthritis
Recent infection with appropriate organism.Oligoarthritis present.Commonly affects weight-bearing joints.May have tendon insertion inflammation and dactylitis (whole digit inflammation).Conjunctivitis, urethritis, and stomatitis may be present.
X-rays may show soft-tissue swelling.
Psoriatic arthritis
Patients usually have a history of psoriasis.Asymmetrical joint distribution.Commonly affects the distal interphalangeal joints.Presence of dactylitis.
Typical radiographic findings include joint erosions, joint space narrowing, bony proliferation including periarticular and shaft periostitis, osteolysis including 'pencil in cup' deformity and acro-osteolysis, ankylosis, spur formation, and spondylitis. [46]

Graft-versus-host disease

Drug rash
Rash may coincide with the timing of recent initiation of antibiotics or following a recent course of chemotherapy or radiation therapy.
Skin biopsy: if the rash does not improve with removing the offending drug, skin biopsy may reveal infiltration of eosinophilic polymorphonuclear leukocytes suggestive of a drug-induced lesion.
Radiation rash
Rash may coincide with the timing of recent radiation therapy.
Clinical diagnosis. No differentiating tests.
Bacterial gastroenteritis
Contaminated food or water. Travel to developing country.
Stool cultures are recommended in order to rule out an infectious cause for the enteritis symptoms that may mimic GI graft-versus-host disease (GVHD).
Viral gastroenteritis
Known infectious contact, or foodborne or waterborne epidemic outbreak.
Stool rapid antigen testing: may detect rotavirus or calicivirus.Stool reverse transcriptase PCR: may detect rotavirus, norovirus, astrovirus, or adenovirus.Stool viral culture and electron microscopy: may detect and identify viral cause.
Neutropenic colitis
Clinically indistinguishable from GVHD.
Abdominal x-ray or abdominal CT scan: may reveal thickening of the colon with fat stranding (an appearance of stranding in peritoneal fat due to inflammation).
Pseudomembranous colitis
Recent antibiotic use.
Stool testing for Clostridium difficile is the first-line diagnostic approach. If this test is negative, colonoscopy or sigmoidoscopy may be warranted.
Crohn's disease
Weight loss, perianal lesions such as skin tags, ulcerations, and fistulae.
Colonoscopy: aphthous ulcers, hyperaemia, oedema, cobblestoning, and skip lesions in Crohn's disease.
Ulcerative colitis
Extraintestinal manifestations such as arthritis, spondylitis, erythema nodosum, pyoderma gangrenosum, uveitis, and episcleritis.
Colonoscopy: rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas (rarely seen), and normal terminal ileum (or mild backwash ileitis in pancolitis) in ulcerative colitis.
Drug-induced enteritis
Enteritis may coincide with introduction of new medications.
Trial drug withdrawal: discontinuation or lowering the dosages of medications known to affect the GI tract may lead to improvement or resolution of abdominal symptoms.
Drug-induced hepatoxicity
Medication history includes drugs with known hepatotoxicity.May include pruritus, arthralgia, headache, and anorexia.
Elevation of liver function tests, including bilirubin, ALT, AST, or alkaline phosphatase.Trial drug withdrawal: discontinuation or lowering the dosages of medications known to be hepatotoxic may lead to improvement or resolution of liver function abnormalities.
Viral hepatitis
Positive for risk factors (e.g., blood transfusion, intravenous drug use, overseas travel).May be recent exposure to infected individuals.
Polymerase chain reaction (PCR) blood tests for viral studies: may detect human herpes virus-6, cytomegalovirus, Epstein-Barr virus, adenovirus, hepatitis B, and hepatitis C.
Veno-occlusive disease (VOD)
Hepatomegaly usually present, RUQ pain, and ascites is the classic triad for VOD.
Liver Doppler ultrasound: shows increased phasicity of portal veins with eventual development of portal flow reversal. The liver is usually enlarged but maintains normal echogenicity.Liver biopsy: required for a definitive diagnosis.
Total parenteral nutrition (TPN) associated cholestasis
Current treatment with TPN.Pale stools and/or dark urine are non-specific findings with cholestasis. Anorexia and decreased appetite may also be present.
Abdominal ultrasound: may reveal gallbladder sludge with mild thickening.Liver function tests: may show elevated AST, ALT, bilirubin, and alkaline phosphatase.Serum triglycerides and cholesterol may also be elevated.Trial withdrawal of TPN may lead to improvement of liver function abnormalities.
Acalculous cholecystitis
Pain often localised to RUQ or jaundice may be presenting signs for acute or chronic cholecystitis.
Liver function tests: may show elevated AST, ALT, bilirubin, and alkaline phosphatase.Abdominal ultrasound: echogenic sludge within a moderately distended gallbladder. No discrete gallstones. The gallbladder wall is not thickened. No biliary ductal dilation.Abdominal CT scan: no gallstones seen. Sludge may be present.Hepatobiliary scintigraphy: highly sensitive (95%) and specific (99%) for diagnosing acute cholecystitis. Serial images show normal hepatic uptake of radiotracer with normal visualisation of common duct and bowel at 30 minutes after injection. The gallbladder is not visualised at 1 hour despite an intravenously administered dose of morphine sulphate.
Polypharmacy and drug interactions
No distinguishing signs or symptoms.
Discontinuation or holding of suspect medication(s) may result in improvement in symptoms.

Granulomatosis with polyangiitis (Wegener's)

Churg-Strauss syndrome
Asthma, prominent gastrointestinal and cardiac involvement.
Significant (>10% of peripheral WBC count) peripheral eosinophilia or tissue eosinophilia.
Microscopic polyangiitis (MPA)
Usually an absence of upper respiratory tract features.
Biopsy reveals a lack of granulomatous inflammation. Note a positive perinuclear (pANCA) versus cytoplasmic ANCA (cANCA) alone cannot be used to distinguish GPA from MPA.
Classic polyarteritis nodosa (cPAN)
Absence of upper or lower respiratory tract involvement.
No glomerulonephritis on renal biopsy.ANCA testing negative.
Cryoglobulinaemic vasculitis
More than 90% of cases are associated with hepatitis C infection.Absence of upper respiratory tract features. Lung involvement rare.
Positive for presence of cryoglobulins in the serum.Rheumatoid factor positive.Reduced serum C4 complement, with normal C3.ANCA testing negative.May show positive serology for hepatitis C (rarely other viruses).Renal biopsy shows mesangioproliferative glomerulonephritis.
Henoch-Schonlein purpura (HSP)
Absence of upper respiratory tract features (although prior history of upper respiratory tract infection common in HSP). Lung involvement uncommon.
ANCA testing negative.Skin or renal biopsy shows IgA deposition on immunofluorescence in HSP.
SLE and other connective tissue diseases (CTDs)
Photosensitive rashes.Alopecia.Features of serositis of pleura, pericardium, or peritoneum.High prevalence of ocular and oral sicca symptoms related to reduced tear and saliva production.Raynaud phenomenon.
Complete blood count typically shows leukopenia and thrombocytopenia.Positive antinuclear antibody (ANA) and anti-double stranded DNA antibody or antibodies against extractable nuclear antigens, favour connective tissue diseases. However, they may show false-positive results for ANCA (by immunoflourescence).
Sarcoidosis
Erythema nodosum.Uveitis.Lymphadenopathy.Splenomegaly.
Chest imaging shows hilar adenopathy.Tissue biopsy shows well-formed non-caseating granuloma without vasculitis.ANCA testing negative.
Systemic infections (e.g., endocarditis, sepsis, bacterial, fungal, or mycobacterial infections)
Presence of a heart murmur warrants exclusion of endocarditis.
Blood cultures positive in endocarditis/sepsis.Echocardiography shows valvular vegetations characteristic of infective endocarditis.Positive autoantibodies, reduced serum complement, immune complex deposition on tissue biopsy, may be seen in endocarditis.Positive tuberculin skin testing seen in tuberculosis.Staining and culture of biological specimens (e.g., sputum, bronchoalveolar lavage fluid) or tissue biopsy specimens (e.g., lung biopsy) positive for microorganisms.Individuals with systemic infections may have false-positive ANCA result.
Goodpasture's syndrome (anti-glomerular basement membrane antibody disease)
The presentation of pulmonary haemorrhage and glomerulonephritis is clinically indistinguishable from GPA.The presence of involvement in other sites (e.g., upper respiratory tract) argues against a diagnosis of anti-GBM antibody disease.
Anti-GBM antibodies positive. Note that a small minority of patients with anti-GBM antibody disease may have a positive ANCA.Lung biopsy fails to show granulomatous inflammation in anti-GBM antibody disease.Lung or renal biopsy shows evidence of (linear) immune deposits in anti-GBM antibody disease.
Cocaine abuse
History of illicit drug use.Cocaine use is associated with perforation of oro-nasal structures including the hard palate.Perforation of structures other than the nasal septum and the lamina papyracea are very rarely seen in GPA.
Urine screening for cocaine.Cocaine users may be cANCA and proteinase 3 antibody (anti-PR3) positive, but may be distinguished from GPA by positive human neutrophil elastase antibody testing.
Medication-induced vasculitis
History of relevant medication use (e.g., propylthiouracil, minocycline).
Usually pANCA positive; may also have antibodies to myeloperoxidase (MPO).
Primary or secondary pulmonary malignancy
A patient with pulmonary malignancy would tend not to have symptoms or signs related to extrapulmonary vasculitis, such as ocular, musculoskeletal, or otorhinolaryngeal manifestations.
Chest imaging findings may be indistinguishable from GPA.Biopsy may allow definitive diagnosis. If a transbronchial biopsy is non-diagnostic, open lung biopsy is required.
Non-Hodgkin's Lymphoma
Usually features palpable lymphadenopathy and/or hepatosplenomegaly (unusual in GPA).May also be associated with cutaneous leukocytoclastic vasculitis or, less commonly, other forms of vasculitis.Natural killer cell lymphomas may lead to midline destructive lesions, mimicking upper airway involvement with GPA.
Lymphoma may rarely be associated with a positive ANCA test.Tissue biopsy (e.g., lymph node) required for definitive diagnosis.

Granuloma annulare

Annular lichen planus
Flat-topped, shiny, violaceous plaques with irregular white streaks called Wickham's striae that may also be seen in mouth and gums. [17]
Skin biopsy: liquefaction degeneration of the basal layer, band-like mononuclear infiltrate of the epidermis, and Civatte' bodies at dermo-epidermal junction.
Dermatophyte infections
Typically unilateral lesions on the fingers associated with an intense pruritus.Worsened by the application of a topical corticosteroid.
Skin scrapings sent for mycology show positive result for dermatophytic infection.
Mycosis fungoides
Generalised or solitary patches or plaques. Can be non-specific in appearance. Very itchy. Long natural history. [14]
Skin biopsy: band-like and patchy infiltrate of atypical lymphocytes (mycosis cells) and positive T-cell rearrangement studies.
Insect bites
Can resemble a papule.Patient may recall insect bite or have relevant travel history.
Skin biopsy: dermal infiltrate predominantly eosinophilic.
Rheumatoid nodule
Tends to occur over bony prominences.Presence of classic features of rheumatoid arthritis, such as hand deformity.
Rheumatoid factor: usually positive if nodules present.
Cutaneous sarcoidosis
May be indistinguishable clinically, as can present in many ways. [18]
CXR: bihilar lymphadenopathy.Serum calcium and angiotensin-converting enzyme levels elevated.Skin biopsy: large islands of epithelioid cells, few giant cells, and occasionally fibrinoid necrosis.
Perforating collagen disorders
Rare. Start as very small lesions and grow over a few weeks into papules.Intensely pruritic.Have a keratinous plug. [19]
Serum urea, creatinine, LFTs, and serum glucose levels may be elevated, as renal failure and diabetes can be associated with the perforating collagen disorders.Skin biopsy: transepidermal elimination of collagen.
Soft-tissue sarcoma
May be indistinguishable clinically.Typically a solitary lump that may have been present for some time.Gradually increasing in size.
Core needle biopsy confirms diagnosis.
Necrobiosis lipoidica
Difficult to distinguish clinically, but patient is likely to have diabetes mellitus (type 1 or 2). Telangiectasia visible centrally.Tender to palpation.
Skin biopsy: inflammatory reaction around destroyed collagen, characteristic appearance.
Erythema migrans
Typical bull's-eye appearance, enlarging area of erythema with central clearing. May have joint pain, fever, and fatigue suggestive of Lyme disease.
Blood test for antibodies to Borrelia burgdorferi but may not be present in the first week after infection.

Graves' disease

Toxic nodular goitre
Hyperthyroidism has gradual onset and is mild in nodular disease. Toxic multinodular goitre usually occurs in an older age group.Nodular goitre is found on physical examination.Extrathyroidal manifestations, such as ophthalmopathy, dermopathy and acropachy are absent.
Peripheral thyroid hormone levels are not usually as high as in Graves' disease.Thyroid receptor antibodies are absent.Thyroid isotopic scan and thyroid ultrasound show nodular goitre.Radioactive iodine uptake is usually normal.
Silent and postpartum thyroiditis
Transient hyperthyroid phase is mostly followed by transient hypothyroid phase. Fifty percent of patients will ultimately develop permanent hypothyroidism in the following years. [47]
Radioactive iodine uptake is very low and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are high.
Subacute thyroiditis
Subacute (granulomatous or de Quervain) thyroiditis starts with thyroid pain and systemic febrile symptoms. Transient hyperthyroid phase followed by transient hypothyroid phase and resolution in few months is typical, with painful thyroid and systemic febrile symptoms. [48]
Radioactive iodine uptake is very low and ESR is high.
Iodine-induced hyperthyroidism
History of iodine exposure is typical. Examples include radiographic contrast or amiodarone.
Increased urinary iodine and low thyroidal uptake of radioactive iodine are typical. [1]
TSH-producing pituitary adenoma
Signs of autoimmunity are absent.
Free T4 and free T3 are elevated, but TSH is inappropriately normal. MRI of the pituitary gland shows a tumour. [49] [50] [51] TSH receptor antibody activity is absent.
Thyroid hormone resistance
The patient may be clinically hypothyroid, euthyroid, or hyperthyroid depending on the type of resistance. Family history is mostly positive for the syndrome, but isolated cases have been reported.
Thyroid hormone levels are elevated with inappropriately normal TSH. [46]Molecular genetic testing is diagnostic.
Inflammatory eye conditions
Inflammatory eye conditions and non-autoimmune causes of ophthalmopathy or proptosis may indicate patient is clinically euthyroid. [3] [42] Ophthalmic findings are more typically unilateral, except in cavernous sinus thrombosis.
MRI or CT scan of orbit suggests a non-thyroidal diagnosis such as orbital myositis, neoplasm or cavernous sinus thrombosis. [1] TFTs are normal. TSH receptor antibody activity is absent.

Groin pain

Hip dysplasia
Caused by intrauterine loss of contact between the fetus' developing femoral head and acetabulum.May range from mild, asymptomatic cases to severe dysplasia with congenital hip dislocation.Moderate to severe dysplasia may predispose to early osteoarthritis, labral tear, or impingement and present with findings secondary to 1 or more of these conditions.Patients with congenital dislocation will have shortening of the involved leg and decreased hip range of motion.
Shallow, more vertically oriented acetabulum seen on plain films.
Nerve entrapment
Rare cause of groin pain.Obturator neuropathy may result in exercise-induced groin pain, relieved by rest. There may be discernible adductor muscle weakness on motor examination if the patient's symptoms are present, and decreased sensation along the medial thigh.Lateral femoral cutaneous nerve entrapment or 'meralgia paraesthetica' typically causes a patch of numbness and/or burning pain along the anterolateral thigh. There is no associated motor weakness with this condition.Ilio-inguinal nerve compression may cause pain in the groin or genital region. It is most commonly seen in patients with a history of prior abdominal surgery or hypertrophic abdominal muscles.
Diagnosis of obturator nerve entrapment can be confirmed by EMG that shows chronic denervation changes along the affected muscle group.Diagnosis of lateral femoral cutaneous or ilio-inguinal nerve entrapment may be made by local infiltration of lidocaine anaesthetic, which should relieve symptoms within minutes.
Ankylosing spondylitis
Spondyloarthropathy typically seen in young to middle-aged men.Hip joint involvement is common, often bilateral.Symptoms (stiffness, pain) are worse in the morning and improve during the course of the day.Low back and sacro-iliac joints are also frequently affected.
Plain film x-rays of the hip and pelvis may demonstrate irregularities of the sacro-iliac joints with possible erosive and sclerotic changes.The lumbar spine may reveal bridging syndesmophytes of multiple vertebrae leading to the classic 'bamboo spine' appearance.
Rheumatoid arthritis
Systemic inflammatory disease with multiple joint involvement.While classically associated with small joints of the hands and feet, hip joint involvement is commonly seen as well.Monoarticular involvement of the hip joint as a presenting symptom in an undiagnosed rheumatoid patient, while rare, can be mistaken for septic arthritis due to the marked inflammatory process and joint synovitis.
Plain film x-rays may demonstrate varying degrees of concentric joint space narrowing, cysts, and periarticular erosions. Unlike in osteoarthritis, osteophytes and sclerotic changes are not typically present.Definitive serological tests, such as rheumatoid factor or anti-citrullinated protein antibodies (ACPA), are positive in around 70% of patients. [15]
Osteoarthritis
Typically seen in patients aged >50 years. Presents with activity-related pain; in advanced cases there may be a component of rest or night pain. Limited range of motion with pain at the extremes (especially flexion and internal rotation). Hip flexion contracture may be present. Positive Stinchfield and/or Trendelenburg sign.
Plain film radiographs with anteroposterior (AP) pelvis, AP and lateral hip, or frog's leg view may demonstrate joint space narrowing, sclerotic and/or cystic changes, and osteophyte formation.
Osteonecrosis
History of recent trauma (femoral neck fracture, hip dislocation) or presence of risk factors (excessive alcohol consumption, chronic corticosteroid use). Bilateral in up to 50% of cases.
Plain film radiographs may be unremarkable in early stage of disease. Later stages characterised by subchondral collapse with formation of a 'crescent sign'.MRI is the definitive test in these circumstances and may demonstrate bony oedema, revascularisation changes seen early in the disease process.
Lumbar disc pathology
Rare cause of groin pain. Upper lumbar disc herniation (L1 or L2) may cause referred pain to groin area.Pain typically worse with Valsalva manoeuvres (e.g., sneezing or bearing down). Back and buttock pain may be present.Hip examination is unremarkable. Motor examination may demonstrate hip flexor weakness. Sensation may be subjectively decreased along dermatomal distribution.
Plain film x-rays of lumbar spine may demonstrate degenerative disc disease of upper lumbar vertebrae.MRI of the lumbar spine should be obtained to rule out disc herniation or foraminal narrowing impinging on corresponding lumbar nerve root.
Septic arthritis
Acute presentation. Joint is usually hot, swollen, and tender, with restricted movement, severe pain on weight-bearing. Fever may be present. More common in joints with a prosthesis. Resting position of hip flexion, abduction, and external rotation may be adopted to relieve pain.
FBC with differential shows raised WBC count. Blood cultures may be positive. ESR and C-reactive protein elevated. Synovial fluid Gram stain and WBC count positive.
Osteomyelitis
Typically a chronic or acute-on-chronic presentation, with vague pain complaints. May have rest or night pain. Constitutional symptoms (fevers, chills, malaise) often present. An unremarkable hip examination possible if the infectious process involves the pelvis.
FBC with differential may show elevated WBC count. Blood cultures may be positive. ESR and C-reactive protein may be elevated.Plain film radiographs may show changes consistent with chronic osteomyelitis in some cases. MRI has higher sensitivity and specificity: up to 98% and 89%, respectively. [16]
Bone malignancy or metastases
Typically results in severe pain, which is often worse at night.
CT/MRI may reveal the metastatic lesion. View image

Group B streptococcal infection

Sepsis caused by other organisms
Escherichia coli and Listeria may cause sepsis in neonates.Other causative organisms include group A streptococcus, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.There are no differentiating signs or symptoms.
Blood or other body fluid cultures positive for specific organism.
Endocarditis caused by other organisms
There are no differentiating signs or symptoms.
Blood or valve tissue cultures positive for specific organism.
Neonatal CMV infection
Cause of neonatal sepsis.There are no differentiating signs or symptoms.
Serology, viral culture, or nucleic acid amplification tests are positive for CMV.
Neonatal HSV infection
Cause of neonatal sepsis.There are no differentiating signs or symptoms.
Viral culture or nucleic acid amplification tests are positive for HSV.
Toxic shock syndrome
There are no differentiating signs or symptoms.
Blood or other body fluid cultures are positive for specific organism (e.g., S aureus, Streptococcus pyogenes).

Growth hormone deficiency in children

Idiopathic short stature
No organic cause.Applies to healthy children with a height more than 2 standard deviation scores (SDS) below the mean for age and sex.
Normal GH provocation tests.No other associated pituitary hormone deficiency.Normal MRI of pituitary.
Constitutional delay in growth
Growth deceleration during the first 2 years followed by a normal growth velocity, with acceleration late in adolescence, leading to a final height that is close to the target height.More frequent in boys; either parent may have been a 'late bloomer'.Patients have a delayed pubertal development.
Delayed bone age.Normal baseline laboratory evaluation.
Familial short stature
Patients are born an adequate size for gestational age.Steady growth below the 5th percentile until reaching a final height that is appropriate for their target height.Puberty is not delayed, and patients are proportionate.
Clinical diagnosis.Normal bone age.
Small for gestational age
Includes patients who are born small for gestational age and have not caught up in height by the age of 2 years but who are otherwise healthy.
Clinical diagnosis.
Hypothyroidism
Most thyroid disorders occur more frequently in girls.May be congenital or acquired.Symptoms include lethargy, fatigue, excessive sleepiness, temperature dysregulation, menstrual abnormalities, and weight gain.Secondary hypothyroidism may co-exist with GHD.
Low free T4 and elevated TSH in primary hypothyroidism.Low free T4 and low TSH in TSH deficiency (pituitary or secondary hypothyroidism).
Turner's syndrome
Characteristic features include ovarian dysgenesis, hearing loss, aortic valve and/or renal abnormalities, and delayed or arrested puberty.Presents only in girls.
Chromosomal abnormality 45 XO, 46/45 XX/XO.
Noonan's syndrome
Short stature with dysmorphic features, congenital heart defects (e.g., pulmonary valve stenosis), and learning problems.
Clinical diagnosis.Genetic testing: may be positive for a mutation in the PTPN11/SOS1/KRAS/RAF1 genes.
Russell-Silver syndrome
Children born small for gestational age with dysmorphism (triangular face, clinodactyly, asymmetry).Feeding problems, hypoglycaemia.
Clinical diagnosis.Genetic testing may reveal maternal uniparental disomy for chromosome 7 (mUPD7) or loss of methylation at 11p15.
Prader-Willi syndrome
Marked hyperphagia, obesity, and learning difficulties.
Deletion of the paternal copy of HBII-85 snoRNAs on chromosome 15q11-13; example of genetic imprinting disorder.
DiGeorge syndrome
Cardiac defects, cleft palate, immune deficiency, hypocalcaemia, and learning difficulties. Also called velocardiofacial syndrome.
Submicroscopic deletion in chromosome 22q11.2.
Failure to thrive
Any chronic medical condition can lead to short stature with or without poor weight gain and failure to thrive. Common conditions include chronic heart disease (congenital or acquired), asthma (moderate or severe), cystic fibrosis, coeliac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), juvenile idiopathic arthritis, chronic renal failure, any chronic malignancy, and poorly controlled diabetes mellitus.
Clinical diagnosis.Specific laboratory test will reveal disease.
Skeletal dysplasia
Achondroplasia, hypochondroplasia, and osteogenesis imperfecta present with disproportionate short stature; dysmorphic features may be present.
Skeletal survey reveals abnormality.
Rickets
Disproportionate short stature, rachitic rosary, bow legs.
Vitamin D is low.Elevated alkaline phosphate.
GH resistance
Insensitivity or resistance to GH results in insulin-like growth factor 1 (IGF1) deficiency and extreme short stature.Difficult to distinguish from GHD clinically.
Normal or elevated basal GH levels.Exaggerated GH response after provocation.IGF generation test reveals the diagnosis.
Craniopharyngioma
Acquired cause of GHD.Rare, suprasellar, cystic tumour that develops from the nests of epithelium derived from Rathke's pouch, an embryonic precursor of the anterior pituitary.Presents with headaches, diplopia, raised intracranial pressure, and pituitary dysfunction.Endocrine dysfunction is variable but typically includes combined pituitary hormone deficiencies and may present pre- or postoperatively. Treatment includes surgery with or without radiotherapy.
MRI brain reveals the solid/cystic suprasellar mass.Pituitary tests show variable pituitary hormone deficiencies.
Child abuse
Acquired cause of a reversible GHD.Children who have been subjected to abuse and neglect present with short stature and a characteristic behavioural pattern that includes hyperphagia, bizarre eating habits that mimic organic compulsive eating disorders, vomiting, and polydipsia.
Normalisation of GH levels on provocation testing after removal from the stressful environment. [24] [51]

Guillain-Barre syndrome

Transverse myelitis
Spinal cord disorders including transverse myelitis present with asymmetrical motor or sensory loss usually involving lower extremities, early bowel or bladder dysfunction with persistent incontinence, and segmental radicular pain.Physical examination demonstrates upper motor neuron signs (hyperreflexia, positive Babinski response) and a sensory level.
CSF analysis: pleocytosis with modest number of lymphocytes and increase in total protein.MRI shows focal demyelination with possible enhancement at the appropriate level. [54]
Myasthenia gravis
Early involvement of muscle groups including extra-ocular, levator, pharyngeal jaw, neck, and respiratory muscles. Sometimes presents without limb weakness.Excessive fatigability and variation of symptoms and signs through the day is common.Reflexes are preserved, and sensory features, dysautonomia, and bladder dysfunction are absent.
Electrophysiological study shows normal nerve conduction and presence of decremental response to repetitive nerve stimulation.EMG shows abnormal jitter and blocking.Edrophonium test is normally positive. [110] However, many centres do not routinely perform this test because of potential side effects.
Lambert-Eaton myasthenic syndrome (LEMS)
Can be difficult to differentiate because of similar clinical characteristics. However, some characteristics are more typical for LEMS. These include slower development of clinical symptoms, dry mouth, lack of objective sensory loss, rare involvement of respiratory muscle group, and potentiation of reflexes after exercise or contraction. [110]
Electrophysiological study: hallmark is a low amplitude compound muscle action potential (CMAP) after single nerve stimulus, increase in CMAP amplitude after voluntary contraction, or repetitive stimulation at high frequencies. [110]
Botulism
History of ingesting food tainted with botulinum toxin.Descending paralysis begins in the bulbar muscles then the limbs, face, neck, and respiratory muscles.Respiratory muscles are involved with mild limb weakness, and reflexes are usually preserved.Ptosis, dilated non-reactive pupils are present. Dilated non-reactive pupils are uncommon in GBS, but it is more common in botulism.Constipation is also a characteristic feature of botulism. [110]
Electrophysiological study: reduced amplitude of evoked muscle potentials, increase in amplitude with repetitive nerve stimulation, and increased number of myopathic units, which is atypical for GBS. [110]
Polymyositis
Presence of pain and muscle tenderness usually in the shoulder and upper arms, involvement of flexor neck muscle disproportionate to limb weakness, absence of sensory symptoms, preservation of reflexes, absence of dysautonomia, and presence of skin lesions, which are uncommon presentation for GBS. [110]
Elevated ESR and CK, normal nerve conduction study, and myopathic changes with fibrillation on EMG.Muscle biopsy shows muscle fibre destruction and regeneration, and lymphocyte infiltrates. [110]
Vasculitic neuropathy
Common features include painful asymmetrical presentation of muscle weakness, uncommon involvement of cranial nerves, respiratory paralysis, and sphincter dysfunction.Usually patients complain of fever, fatigue, weakness, and arthralgia. [110]
May have elevated ESR.CSF does not show albuminocytological dissociation.Electrophysiological study shows evidence of denervation.Nerve biopsy shows signs of inflammation and scarring. [110]

Gynaecomastia

Breast cancer
Risk of both gynaecomastia and breast cancer increased in high oestrogen states.Men with family history of the BRCA2 gene mutation, prostate cancer, or Klinefelter's syndrome at higher risk.Malignancy should be considered if the breast mass is unilateral, although gynaecomastia can be unilateral and breast cancer bilateral.Breast cancer is usually painless, but not always. The mass may be eccentric (10% to 30%) rather than sub-areolar. The mass often is irregular, rather than smooth; rubbery or hard rather than firm; and fixed rather than mobile.Any overlying nipple deformity or ulceration or discharge; red, thickened, or ulcerated overlying skin; or axillary adenopathy raises suspicion for malignancy.
Any eccentric, irregular, hard, or fixed mass, or associated nipple or skin abnormality, or axillary adenopathy, mandates a biopsy.A core biopsy is preferred. [34] View imageMammography is 90% specific and 90% sensitive for a malignant mass in men. [35]
Benign breast masses
Bilateral or painful masses more likely benign.
Breast biopsy demonstrates histological findings of the underlying disorder.Rare non-malignant conditions include lipoma, lupus mastitis, granulomatous mastitis, haemangioma, or hamartoma.
Pseudo-gynaecomastia
Pincer-like compression of the breast against the chest wall reveals no mound of firm breast tissue extending beyond the nipple.
Not usually necessary.Mammogram or ultrasound can differentiate gynaecomastia from adipose tissue and is helpful if cosmetic surgery is planned. [35]
Metastatic tumour
Hx of smoking, unexplained weight loss, liver disease, or cancer may be clues to metastatic activity.Malignancy should be considered if the breast mass is unilateral, although gynaecomastia can be unilateral and breast cancer bilateral.Any overlying nipple deformity or ulceration or discharge; red, thickened or ulcerated overlying skin; or axillary adenopathy raises suspicion for malignancy.
Breast biopsy demonstrates histological findings of the primary disorder.Rare malignancies include metastases from lung, prostate, or liver cancer; Hodgkin's or non-Hodgkin's lymphoma; or plasmacytoma.

Haemangioma

Venous malformation
Blue or purple colour.Present at birth.Soft and compressible on examination. Proportionate growth.Non-pulsatile.Size may readily increase with dependent positioning.No spontaneous involution.May ache but is not usually tender. Thrombosis may cause acute swelling and tenderness.Phleboliths may be palpable as hard masses. [47] [48]
Doppler ultrasound of lesion shows a sponge-like array of anechoic vessels with a venous waveform. [36]MRI with and without contrast shows venous lakes and phleboliths. [49]Laboratory studies may show low serum fibrinogen, elevated D-dimer, and low platelet counts indicative of chronic intravascular coagulopathy. [1]X-rays may show calcified phleboliths. [47] [48]
Arteriovenous malformation
Blue or red colour.Present at birth.Proportionate growth.No spontaneous involution.May cause ulceration, pain, and claudication due to vascular steal.Warm and pulsatile. [48] [50]
Ultrasound with Doppler shows numerous vessels with arterial and venous wave forms. [36]MRI with and without contrast shows high flow, serpiginous signal voids, and possible intra-osseous extension. [49]
Lymphatic malformation
Large, translucent soft mass with normal overlying skin colour.Usually present at birth or before 2 years of age.Proportionate growth.No spontaneous involution.May swell with prolonged dependent positioning. [48]
Doppler ultrasound of lesion shows a poorly defined collection of cysts with a high mean restrictive index. [36]MRI with and without contrast shows no vessels or lobular architecture. Contrast enhancement is absent. [38]
Rapidly involuting congenital haemangioma (RICH)
Fully formed at birth and involutes over the first year of life. [51] [46]
Standard histology shows prominent capillary lobules surrounded by fibrous tissue.Central involuting zones with lobular loss, fibrous tissue, and abnormal draining channels. [52]GLUT1 staining negative. [44] [52] GLUT1 is an erythrocyte-type glucose transporter present in infantile haemangioma, brain, and placenta. [44] [45] [46]
Non-involuting congenital haemangioma (NICH)
Fully formed at birth and does not involute. [46] [52]
Standard histology shows prominent capillary lobules and associated thin-walled vessels within densely fibrotic stroma. These lobules also show thrombosis, haemosiderin deposits, and sclerosis. [46]GLUT1 staining negative. [44] [46] GLUT1 is an erythrocyte-type glucose transporter present in infantile haemangioma, brain, and placenta. [44] [45] [46]
Kaposiform haemangioendothelioma
Congenital skin-coloured, red or purple plaques or masses that resemble lymphatic malformations.Life-threatening consumptive platelet trapping with acute tenderness, erythema, and swelling (Kasabach-Merritt phenomenon).No spontaneous involution. [19]
Standard histology shows infiltrative stands of thin endothelial cells that line slit-like vessels.Eosinophilic epithelioid cell nests are interspersed. [10]
Fibrosarcoma
Vascular-appearing tumour that mimics an infantile haemangioma.Congenital, typically on extremities.Displays rapid growth.No spontaneous involution. [1] [53] [54] [55] [56]
Standard histology shows densely packed, uniform, spindle-shaped cells.Mitoses common.Tumour is largely avascular microscopically. [53] [54] [55] [56]
Capillary malformation
Present at birth or soon after.Pink macules and patches remain flat. [10]
The diagnosis is made on clinical follow-up.Biopsy is rarely performed, but histology shows an increased number of dilated vessels. [10]
Tufted angioma
Mottled red colour with flat and papular areas.Growth is slow over months to years.Lesions extend laterally.Associated with life-threatening platelet trapping, the Kasabach-Merritt phenomenon (consumptive platelet trapping with acute tenderness, erythema, and swelling). [57]
Standard histology shows separate capillary lobules that look like cannonballs within the dermis and subcutaneous tissue.Negative for GLUT1 staining. [57] GLUT1 is an erythrocyte-type glucose transporter present in infantile haemangioma, brain, and placenta. [44] [45] [46]

Haemochromatosis

Iron overload from chronic transfusion
History of chronic transfusion would help differentiate.
Patients with iron overload from chronic transfusion are much more likely to be anaemic at the time of diagnosis; therefore, an FBC is recommended.
Dysmetabolic hyperferritinaemia
Common syndrome that presents in patients with metabolic syndrome (obesity, hypertension, hyperlipidaemia, type 2 diabetes mellitus, and hyperuricaemia) and high ferritin levels.
Can present with an raised serum ferritin, low transferrin saturation, mild hepatic iron overload on biopsy or MRI (lower than expected when compared with serum ferritin), and mixed iron deposition in both hepatocytes and macrophages on liver biopsy.
Hereditary aceruloplasminaemia
Very rare yet familial. Can be associated with diabetes and often is associated with a neurological syndrome (extrapyramidal syndrome, cerebellar ataxia, retinal degeneration, and dementia).
These patients have marked elevation of the serum ferritin (without evidence of inflammation), but have low transferrin saturation and can have severe hepatic iron overload. The diagnosis requires documentation of undetectable levels of serum ceruloplasmin.
Excessive iron supplementation
History of excessive iron supplementation, especially with excessive vitamin C supplementation.
These patients would not have a homozygous gene mutation associated with hereditary haemochromatosis.
Chronic hepatitis
History of risk factors for hepatitis
Patients would have hepatitis panels consistent with chronic viral hepatitis (especially hepatitis C) and would not have homozygous mutations consistent with hereditary haemochromatosis. [33]

Haemolytic anaemia

Anaemia due to blood loss
History and physical examination will often identify source of blood loss.
Normal haptoglobin, bilirubin, and LDH.Microcytic anaemia. Iron deficiency.Faecal occult blood test may be positive.
Underproduction anaemia
Due to decreased RBC production from multiple causes, such as bone marrow failure (myelofibrosis, myelodysplastic syndrome, myelosuppression, aplastic anaemia), anaemia of chronic disease, and deficiency states (iron, vitamin B12, folate). Clinical evaluation depends on underlying cause.
Reticulocyte count is low, signs of haemolysis typically absent.
Transfusion reaction
Acute reactions occur during or immediately following blood transfusion.Symptoms of acute reactions may include: chills; fever; headache; pallor; pain along the infusion site; abdomen, back or chest pain. Signs of acute reactions may include: pruritus; flushing; dyspnoea; urticaria; hypotension; haemoglobinuria; wheezing; and stridor.There may be a history of prior exposures to foreign red-cell antigen following pregnancy, previous transfusion, or organ transplantation with delayed haemolytic transfusion reactions. Symptoms and signs occur days to weeks following a transfusion, and include: pallor; jaundice; haemoglobinuria; purpura; bleeding (DIC).
Direct antiglobulin (Coombs) test may be positive and serum haptoglobin low, as for haemolysis generally.Visual inspection of post-transfusion sample may show pink-to-red colour.Testing may show ABO incompatibility between recipient and donor.In cases of anaphylactic reaction, serum IgA levels may be low and anti-IgA antibodies may be positive.

Haemolytic uraemic syndrome

Thrombotic thrombocytopenic purpura (TTP)
Although this has historically been described as presenting with a higher incidence of neurological symptoms and a lesser degree of renal failure than HUS, there is so much overlap between the two that some experts recommend treating them as a single entity. [2] The seminal discovery of low levels of the von Willebrand cleaving enzyme, ADAMTS13, in many patients with presentations typical of TTP but not those with typical of HUS suggests that there are distinct pathophysiological mechanisms involved. [31]
Levels of the von Willebrand cleaving enzyme, ADAMTS13, whose deficiency is implicated in the pathogenesis of TTP, are more consistently low in TTP than in HUS, [30] but this has not yet been translated into clinical practice decisions. [2]
Malignant hypertension
This can have pathological features of thrombotic microangiopathy with similar characteristics to those of HUS; therefore, consideration of malignant hypertension as a differential diagnosis is required. [2] The distinguishing feature is a significantly elevated blood pressure. [32]
Platelet counts are generally normal in malignant hypertension. [32]
Vasculitis
A pre-existing diagnosis or a history of symptoms suggestive of a rheumatological condition mandates that vasculitis be considered in the diagnosis. However, there are many overlapping features between SLE and TTP/HUS, and since the two can co-exist, a distinction between them is generally not possible. [33]
Serological tests of underlying condition may be positive, but there are no tests to differentiate the cause of HUS.
Catastrophic antiphospholipid syndrome
This condition can present in a way that is indistinguishable from TTP/HUS. [34] [35]
Antiphospholipid antibodies can be helpful in suggesting a diagnosis. However, even if these are positive, plasma exchange is often recommended in patients with manifestations of severe disease. [35]
Disseminated intravascular coagulation
Patients with DIC have a higher likelihood of bleeding manifestations and often have obvious predisposing causes, such as sepsis.
The peripheral smear in a patient with DIC generally has fewer schistocytes. Coagulation parameters are typically abnormal in patients with DIC, whereas they are normal in patients with TTP/HUS.
Pre-eclampsia
Distinguishing between the various causes of thrombocytopenia that present in the peri- and post-partum period can be difficult if not impossible. [21] [22] HUS tends to present post-partum, which distinguishes it from pre-eclampsia.
The peripheral smear in patients with TTP/HUS generally has more schistocytes than are seen in pre-eclampsia.
HELLP syndrome
HUS tends to present post-partum, which distinguishes it from HELLP (haemolysis, elevated liver enzyme levels, and a low platelet count) syndrome.
The peripheral smear in patients with TTP/HUS generally has more schistocytes than are seen in HELLP syndrome.

Haemophilia

Acquired haemophilia
A much rarer condition that presents most frequently in the older adult (>60 years of age).Patients are more likely to have other associated conditions such as autoimmune disorders, inflammatory bowel disease, diabetes, hepatitis, pregnancy, and malignancy.May present with bleeding into the skin (purpura), soft tissues, and mucous membranes. [32]Musculoskeletal bleeding is less common than with congenital haemophilia.
Factor VIII levels are low, with positive factor VIII inhibitor.Unlike congenital haemophilia, the aPTT does not correct by mixing with normal plasma (mixing study). This is due to the presence of inhibitory antibodies.
Von Willebrand disease (VWD)
Family history is usually positive, including both females and males, due to an autosomal dominant pattern of inheritance.Bleeding symptoms may be similar to mild congenital haemophilia, although patients with von Willebrand disease tend to have more mucosal bleeding symptoms.
Diagnosis is based on various tests, including von Willebrand factor (VWF) antigen, VWF activity (ristocetin cofactor or collagen-binding assay), factor VIII assay, and VWF multimers.Most clinicians agree that VWF levels <30 international units/dL are consistent with a diagnosis of von Willebrand disease. [28] However, repeated testing is often needed to confirm the diagnosis.
Platelet dysfunction
Bleeding pattern is typically mucocutaneous and not musculoskeletal as in haemophilia.
Platelet aggregation studies are the diagnostic test of choice to diagnose most platelet disorders. [31]Specific platelet agonists (ADP, adrenaline, collagen, ristocetin, and arachidonic acid) are used to assess platelet aggregation by measuring optical density.Platelet electron microscopy can also be used to evaluate platelet ultrastructure.
Deficiency of other coagulation factors (e.g., factor V, VII, X, XI, or fibrinogen)
Musculoskeletal bleeding is uncommon.Factor V mutations are associated with the occurrence of thrombosis.There have also been cases of thrombosis reported in people with factor VII deficiency.
Specific coagulation factor assays are needed to establish diagnosis.
Ehlers-Danlos syndrome
Bleeding is primarily mucosal in origin.Musculoskeletal bleeding is uncommon.Skin hyperextensibility, joint laxity present.
Diagnosis based on clinical findings, along with genetic testing and/or tissue biopsy.
Scurvy
Bleeding is primarily mucosal in origin.Musculoskeletal bleeding is uncommon.History of a restricted diet, sepsis, HIV, critical illness, or pancreatitis may be present.
Diagnosis based on clinical findings, along with a reduced serum vitamin C level.
Fabry's disease
Bleeding is primarily mucosal in origin.Musculoskeletal bleeding is uncommon.Typical skin lesions (angiokeratomas), pain in the extremities, renal and heart disease, typical ocular signs.
Diagnosis based on clinical findings, along with genetic testing.
Child abuse
Inconsistent history of how trauma occurred is typical.Physical examination may show injuries in various healing stages or with an obvious pattern, bruises, inflicted burns, fractures.
FBC may reveal anaemia, which may be chronic in neglected or malnourished children.Liver and pancreatic enzymes may be elevated if abdominal trauma.Imaging may reveal abnormal x-rays with evidence of fractures, or abnormal brain or abdominal imaging due to bleeding.

Haemorrhagic stroke

ischaemic stroke
Symptoms occur suddenly.In ischaemic stroke, patients do not exhibit GI symptoms (N/V) or headache typically.
Acute haemorrhage appears bright due to hyperattenuation of the x-ray beams. In contrast, ischaemic infarct appears as hypoattenuation (darkness), although may not appear for many hours after stroke onset.
hypertensive encephalopathy
HTN significantly above patient's baseline BP associated with headache, decreased consciousness or cognitive abnormalities, visual changes or loss, and signs of increased intracranial pressure.
Cerebral oedema on CT or MRI.
hypoglycaemia
Sweating, tremor, hunger, confusion, and ultimately a decreased level of consciousness.May have known history of diabetes mellitus and insulin use or medical conditions associated with hypoglycaemia.
Low serum glucose on blood chemistry.
complicated migraine
Repetitive history of similar events preceding aura; headache in a marching pattern.
MRI shows no evidence of infarction.
seizure disorder
A history of seizures and/or a witnessed seizure followed by postictal deficits.
EEG results may identify seizure activity.MRI shows no evidence of infarction.
conversion and somatisation disorders
Neurological signs and symptoms do not fit a vascular territory. No cranial nerve deficits.Additionally, conversion disorder displays multiple signs that are neurologically inconsistent.
CT and MRI show no evidence of infarction or haemorrhage in conversion disorder.

Haemorrhoids

Anal fissure
Anal fissures are associated with painful bleeding on defecation and possibly a sentinel skin tag (sometimes reported by the patient as a “painful haemorrhoid”). Fissures are seen as linear tears in the anal mucosae, most commonly in the posterior midline of the anal canal.
Physical examination.
Crohn's disease
Crohn's disease affecting the large bowel can present with rectal bleeding and is associated with diarrhoea rather than constipation. Family history of inflammatory bowel disease is often present.
Endoscopy findings highly variable, depending on disease activity. Characteristically shows 'skip areas' with areas of disease with intervening areas of normal mucosa. Usually most severe in the cecum and right colon, with rectum often spared.
Ulcerative colitis
Ulcerative colitis commonly presents with rectal bleeding and is associated with diarrhoea rather than constipation. Family history of inflammatory bowel disease is often present.
Endoscopy reveals diffuse inflammation and ulceration in cases of acute ulcerative colitis.
Colorectal cancer
History of altered bowel habits, anaemia, colonic polyps, and positive family history suggest colorectal cancer.
Endoscopy may reveal mass, stricture, and obstruction. Blood tests commonly reveal anaemia.
Anal fistula
Commonly bleeding with a history of a preceding abscess, with continued intermittent bloody/purulent drainage. Visualised as a punctuate opening on the anal margin adjacent to the anal canal.
Physical examination.

Hairy cell leukaemia

Chronic lymphocytic leukaemia (CLL)
Clinically, CLL and HCL are indistinguishable.
Typically, the abnormal B cell in CLL stains positive for the antigen CD5, which is expressed rarely in HCL. The antigen CD103, which is expressed commonly in HCL, is not expressed in CLL. [21] [27] Typically, mantle cell lymphoma and HCL cells stain negative for CD23 antigen, which is found commonly on CLL cells. Over-expression of cyclin D1 owing to t(11;14) chromosome translocation is a hallmark of mantle cell lymphoma. However, weak expression of cyclin D1 can also be detected in HCL. [1] [23] [28]
Mantle cell lymphoma
Clinically, mantle cell lymphoma and HCL are indistinguishable.
Over-expression of cyclin D1 owing to t(11;14) chromosome translocation is a hallmark of mantle cell lymphoma. However, weak expression of cyclin D1 can also be detected in HCL. [1] [23] [28] Typically, the abnormal B cell in mantle cell lymphoma stains positive for the antigen CD5, which is expressed rarely in HCL. Typically, mantle cell lymphoma and HCL cells stain negative for CD23 antigen, which is found commonly on CLL cells.
Pro-lymphocytic leukaemia
Clinically, pro-lymphocytic leukaemia and HCL are indistinguishable.
Pro-lymphocytic leukaemia is distinguished from HCL by a marked elevation of WBC count, as opposed to pancytopenia, together with the distinct morphology of pro-lymphocytes on histological examination. [21] [28]
Splenic marginal zone lymphoma (SMZL)/splenic lymphoma with villous lymphocytes (SLVL)
Clinically and morphologically, HCL and SMZL/SLVL are indistinguishable.
SMZL/SLVL cells do not display tartrate-resistant acid phosphatase (TRAP)-positivity and the bone marrow infiltrates are demarcated sharply. The immunophenotype profile displays negative staining for CD103, CD27, and CD25. [21] [28] CD11c is expressed commonly in B-cell chronic lymphocytic leukaemia (B-CLL), splenic marginal zone lymphoma, and HCL, although the intensity of expression is 30-fold greater in HCL than in B-CLL and SMZL/SLVL. [21] Annexin A1 is negative in SMZL/SLVL, whereas it is positive in HCL.
Aplastic anaemia
Clinically, aplastic anaemia and HCL are indistinguishable.
Practitioners should beware erroneous diagnosis of aplastic anaemia owing to dry-tap bone marrow aspirate with hypo-cellular bone marrow. Immunostaining for B-cell antigens is essential and can prompt more specific immunophenotyping for HCL. [1]
Variant hairy cell leukaemia (HCL-v)
The patients typically present with leukocytosis with an average WBC around 35,000 per microlitre. Splenomegaly is common.
Unlike in HCL, the absolute monocyte count is usually normal and cells lack several key antigens seen in HCL: CD25, Annexin A1, CD123, CD25; the cells are also TRAP-negative. HCL-v cells can be, however, positive for DVA.44 (CD72), CD11c, pan-B-cell antigens, CD103, FMC7, and express monotypic surface immunoglobulin. Patients with HCL-v typically do not respond as well to standard HCL treatment.

Hand-foot-and-mouth disease

Aphthous stomatitis or oral aphthous ulcers
Ulcers are on the mucosal surfaces of the mouth.The child is well, with no fever, malaise, or rash.
Diagnosis is clinical.
Herpes simplex
In most cases, there is a high fever, >38°C (>100.4°F).Acute gingivitis and widespread oral ulceration are present.On the skin, the vesicles are small and oval, on an erythematous base, and grouped together.Usually no rash on the palms and soles, although young children who suck their fingers or toes may have lesions on 1 or 2 digits. [8]
A Tzanck smear of vesicle fluid will show multi-nucleated giant cells.A direct fluorescent antigen test for herpes simplex virus can also be done.These tests are rarely indicated as the diagnosis can usually be made clinically.
Herpangina
Cervical lymphadenopathy is present, and ulcers are also seen on the soft palate.A rash does not usually occur. [8]
Diagnosis is clinical.
Chickenpox
The rash is usually limited to the trunk and extremities and highly pruritic. The classic lesion is a round vesicle on an erythematous base that evolves into a pustule. [8]
A direct fluorescent antigen test for varicella virus.

Hantavirus cardiopulmonary syndrome

Viral upper respiratory tract infection
Sinus congestion, rhinorrhoea.Rhinorrhoea and sinus congestion are not features of hantavirus infection.
Clinical diagnosis.
Influenza pneumonia
Influenza is commonly associated with upper airway symptoms.
Influenza antigen testing and respiratory virus cultures are positive for influenza.
Mycoplasma pneumoniae pneumonia
Dry, persistent cough. Bullous myringitis may be present.Clinical response to appropriate antibiotic therapy.
Serum cold agglutinins may be positive in Mycoplasma infection.
Chlamydia pneumoniae pneumonia
Upper respiratory symptoms and gradual onset of the infection.Clinical response to appropriate antibiotic therapy.
Positive culture for C pneumoniae.Serological tests for C pneumoniae can be diagnostic.
Histoplasmosis
Histoplasma capsulatum proliferates in soil contaminated with bird or bat droppings. Exposure is commonly associated with cave exploration, close proximity to chicken roosts, demolition, and excavation. High concentration aerosol inocula can cause a diffuse pneumonia.May be clinically indistinguishable.
Positive culture and antigen testing.
Coccidioidomycosis
Fungal pneumonia caused by Coccidioides immitis may be clinically indistinguishable.May have associated rash.
Positive serology for coccidioidomycosis.
Leptospirosis
Conjunctival suffusion, hepatic involvement, most commonly a self-limiting illness.Clinical response to appropriate antibiotic therapy.
Leptospirosis serological testing positive.
Psittacosis
History of exposure to domesticated or commercially raised birds, mammals, and exotic imported birds.Splenomegaly is occasionally present.Clinical response to appropriate antibiotic therapy.
The diagnosis may be made serologically from paired sera for psittacosis-antibodies.
Q fever pneumonia
Caused by Coxiella burnetii infection (commonly of livestock and domestic animals) and exposure to contaminated soil or dust.May be clinically indistinguishable.
Immunofluorescence assay (IFA) of infected tissue is positive.
ARDS
May be clinically indistinguishable.
Both ARDS and hantavirus cardiopulmonary syndrome (HCPS) produce diffuse air space disease on CXR. Experienced radiologists may be able to distinguish between the 2 syndromes after viewing serial x-rays. [41]
Myocardial infarction
Distinguishable by lack of fever.
ECG changes of acute ischaemia, and elevated levels of troponin and CK.
Bacterial sepsis
May be clinically indistinguishable, but history and examination may reveal primary source of infection.
Blood cultures are usually positive in bacterial sepsis.Haemodynamic measurements demonstrate increased peripheral vascular resistance (PVR) with hantavirus infection versus decreased PVR in septic shock.
Plague
High fevers, purple skin patches, vomiting, seizures, shock.
Blood, urine, sputum, and fluid from buboes or other lesions to identify bacteria.CXR will show patchy areas in the lungs in pneumonic plague.
Rickettsial disease
Recent tick exposure; triad of fever, maculopapular or petechiae rash, and headache.
Indirect IFA: titre ≥1:64.Serum electrolytes: low sodium; elevated urea.
Pneumocystis jiroveci pneumonia
History of prior Pneumocystis pneumonia, HIV-positive, oropharyngeal candidiasis, recurrent bacterial pneumonia, weight loss.
CXR: bilateral symmetrical interstitial infiltrates.Induced sputum: positive for Pneumocystis.

Heat stroke

Delirium
Altered attention level.Not typically associated with elevated core temperature, although patients with heat stroke may have delirium in addition to pyrexia.
Diagnostic distinction is typically based on clinical examination.Significant abnormalities from laboratory investigations are lacking.
Meningitis
Headache, fever, nuchal rigidity, occasional CNS alteration.
LP is generally abnormal in patients with meningitis.
Diabetic ketoacidosis (DKA)
Altered level of consciousness or alertness, hyperventilation, myriad other non-specific systemic symptoms.
Plasma glucose is typically severely elevated in patients with DKA; ketones in urine.
Hyperthyroidism
Common signs include tachycardia, exophthalmos, hyper-reflexia.Symptoms are typically of more insidious onset in patients with hyperthyroidism.
TSH is low; elevated T3 and T4.
Neuroleptic malignant syndrome (NMS)
Generally preceded by a typical event, such as receiving anaesthetic agents.Responsive to dantrolene.
Diagnosis is clinical; elevated CK.
Drug toxicity
Medicine/drug overdose may present with hyperthermia but not be associated with elevated ambient temperature or physical activity.Often there is a history of drug use or of recent ingestion.Drugs commonly associated include cocaine, phencyclidines, and salicylates.
Blood assays positive for the ingested agent.
Delirium tremens
May present with hyperthermia but not be associated with elevated ambient temperature or physical activity.Typically associated with history of alcohol abuse without recent ingestion. Often there is a clinical history of prior withdrawal symptoms.
LFTs may be elevated.

HELLP syndrome

Acute fatty liver of pregnancy
Also occurs in the third trimester of pregnancy or postpartum, and may be difficult to distinguish from HELLP.Patients may have hypertension and/or proteinuria, although not frequently.
Total bilirubin is increased much more than in HELLP syndrome, to levels in excess of 4 mg/dL. The direct fraction of bilirubin is increased (unlike in HELLP syndrome, in which the indirect bilirubin fraction is increased).Coagulopathy ( hypofibrinogenaemia, prolonged PT, low antithrombin) is usually present early in the disease (unlike in HELLP syndrome, in which coagulopathy develops in the late stages).Liver transaminases are generally <500 units/L, although in some severe cases may exceed 1000 units/L.Hypoglycaemia (not typically present in HELLP unless there is liver failure) is a key distinguishing factor, as is leukocytosis (>130 x 10^9/L [>13,000/microL] with left shift). There may also be haemoconcentration, metabolic acidosis, increased ammonia, and elevated serum creatinine (mean 203.3 micromol/L [2.3 mg/dL]) and uric acid (mean 654.3 micromol/L [11 mg/dL]). [23]Liver biopsy is the standard for confirming the diagnosis, but it is rarely used in clinical practice.
Thrombotic thrombocytopenic purpura (TTP)
Can be difficult to distinguish from HELLP.Classic pentad of TTP consists of thrombocytopenia, haemolytic anaemia, neurological abnormalities, fever, and renal impairment.However, neurological abnormalities may be non-specific (such as headaches, visual changes, weakness, and seizures) and therefore difficult to diagnose and to distinguish from HELLP syndrome.Presenting features may also include abdominal pain, hypertension, nausea, and vomiting, in conjunction with jaundice, petechiae, purpura, or other abnormal bleeding.
Thrombocytopenia is more severe than in HELLP syndrome (<25 x 10^9/L [<25,000/microL]) and often requires transfusion.Liver transaminases increase less than they do in HELLP syndrome, usually there is no coagulopathy, and antithrombin levels are unchanged.Maternal condition does not improve with delivery. [24]ADAMTS13 (a von Willebrand's factor-cleaving metalloprotease) is markedly reduced (to >5% of normal) in most patients with congenital TTP, and antibodies that neutralise ADAMTS13 have been found in women with acquired TTP. However, testing for ADAMTS13 is not readily available in most clinical laboratories. [25]
Haemolytic uraemic syndrome (HUS)
Rarely associated with pregnancy; almost universally occurring in the postpartum period (up to 10 weeks). [26]
Presentation is similar to that in TTP, both being characterised by micro-angiopathic haemolytic anaemia and thrombocytopenia. In HUS, the microvascular injury mainly affects the kidneys, renal function deterioration being more significant than in TTP and HELLP, and haemolysis may also be prominent, frequently requiring blood transfusions.There are no coagulation abnormalities [26] [27] and antithrombin levels are unchanged.Liver transaminases are less elevated than they are in HELLP syndrome.
Cholestasis of pregnancy
Severe generalised pruritus, mild jaundice, mild epigastric pain, steatorrhoea, and dark urine are among the most common findings.
Mild elevations of liver transaminases, rarely >250 units/L, but increased alkaline phosphatase, hyperbilirubinaemia (predominantly conjugated) up to 6 times greater than normal, and markedly elevated (10-fold to 100-fold) total serum bile acids. The diagnosis of cholestasis is unlikely if the total bile acids are <8 micromol/L. [28]

Hemangioendothelioma

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Henoch-Schonlein purpura

Idiopathic thrombocytopenic purpura (ITP)
Rash of ITP may also have petechiae. Arthralgias and abdominal pain are uncommon.
Platelet level is low in ITP, but normal in HSP.
Hypersensitivity vasculitis
Usually no renal involvement.
Skin biopsy may show leukocytoclastic vasculitis, but no IgA deposition.
Wegener's granulomatosis
May have similar clinical features to HSP, but uncommon in children.
Predominance of deposition of IgA on biopsy characterises HSP.Laboratory evaluation including antinuclear antibodies, antineutrophil cytoplasmic antibodies, and complement levels can help differentiate HSP from other vasculitides.
Systemic lupus erythematosus (SLE)
May have similar clinical features to HSP, but uncommon in children.
Predominance of deposition of IgA on biopsy characterises HSP.Laboratory evaluation including antinuclear antibodies, antineutrophil cytoplasmic antibodies, and complement levels can help differentiate HSP from other vasculitides.
Rheumatoid arthritis
May have similar clinical features to HSP; however, the rash in rheumatoid arthritis, if present, is usually not palpable purpura. Rheumatoid arthritis is seen more often in adults.
Predominance of deposition of IgA on biopsy characterises HSP.Rheumatoid factor has been reported in both rheumatoid arthritis and HSP, therefore making them difficult to distinguish.
Rheumatic fever
May have similar clinical features to HSP; however, the rash in rheumatic fever is erythema marginatum, and not palpable purpura.
Predominance of deposition of IgA on biopsy characterises HSP. Increased anti-streptolysin-O antibody titres have been reported in both rheumatic fever and HSP, therefore making them difficult to distinguish.
Meningococcal septicaemia
May have similar clinical features; rash may also have petechiae.
Abnormal coagulation studies and low platelet counts are seen in septicaemia. These studies are normal in HSP.
Haemolytic uraemic syndrome (HUS)
May have similar clinical features; rash may also have petechiae. Diarrhoea is common in HUS.
Haemolytic anaemia, with elevated reticulocyte counts and low haptoglobin levels, and low platelets are seen in HUS. Stool studies may be helpful in HUS; these studies are normal in HSP and abnormal in HUS.
Polyarteritis nodosa
May have similar clinical features to HSP, but uncommon in children.
Predominance of deposition of IgA on biopsy characterises HSP.Laboratory evaluation including antinuclear antibodies, antineutrophil cytoplasmic antibodies, and complement levels can help differentiate HSP from other vasculitides.
IgA nephropathy
Rash, abdominal pain, and arthritis are generally not present. Patients are usually between 20 to 40 years of age.
Renal biopsy shows similar findings with IgA nephropathy and HSP. However, patients with IgA nephropathy do not have the other clinical manifestations of HSP.
Other vasculitides
May have similar clinical features to HSP, but uncommon in children.
Predominance of deposition of IgA on biopsy characterises HSP.Laboratory evaluation including antinuclear antibodies, antineutrophil cytoplasmic antibodies, and complement levels can help differentiate HSP from other vasculitides.

Hepatic encephalopathy

Brain tumours
Focal neurological signs.
Head CT scan may show space-occupying lesion.
Subdural haematoma
History of trauma, focal neurological signs.
Head CT scan may show haemorrhage.
Acute stroke
Neurological examination may show focal neurological deficits in HE, but these are more common in stroke.
Head CT scan may show haemorrhage or infarct.
Meningitis
Headache, photophobia, neck stiffness, nausea, fever.
Lumber puncture may show cloudy cerebrospinal fluid with increased white blood cells and protein, and reduced glucose in meningococcal meningitis.Organisms may be found on Gram stain and culture.MRI may show meningeal enhancement.
Encephalitis
Patient may have fever, headache, or history of infection (e.g., measles).
Temporal lobe involvement on MRI is highly suggestive of HSV encephalitis.Cerebrospinal fluid may be normal or show lymphocytes.
Uraemia
History of renal disease or failure, fatigue, weakness.Pallor, oedema, hypertension, dyspnoea, leg cramps, asterixis, and peripheral neuropathy may be present.
Raised serum blood urea nitrogen and creatinine are consistent with renal dysfunction and uraemia.
Hyper- or hypoglycaemia
History of diabetes and hypoglycaemia are more common in older patients or those attempting tight control.Differentiating features include signs of autonomic overactivity, sweating, tachycardia, and coma. Diabetic ketoacidosis may be preceded by polyuria, nausea, and confusion. Patients may have fruity, acetone breath, tachycardia, and abdominal pain.Hyperglycaemia may occur in absence of ketones and may also cause metabolic encephalopathy.
Serum glucose should be measured, as both hyperglycaemia and hypoglycaemia can cause metabolic encephalopathy.
Hypercarbia
Signs of chronic respiratory failure.
The normal level of PaCO2 is generally accepted to be between 35 and 45 mmHg.High levels can cause mental status changes.
Benzodiazepine overdose
History of depression and suicidality may be present.
Trial of flumazenil in selected patients may diagnose benzodiazepine overdose.
Tricyclic antidepressant overdose
Tachycardia, hypotension may be present.
ECG shows terminal 40-ms rightward axis deviation, seen as an R-wave deflection in aVR or an S-wave in lead I or aVL.
Wernicke's encephalopathy
Characterised by encephalopathy, oculomotor dysfunction (nystagmus, gaze palsy), and gait ataxia.
MRI may show increased T2 and decreased T1 signalling surrounding the aqueduct and third ventricle, and within the thalamus and mamillary bodies (53% sensitivity, 93% specificity). [20]
Spontaneous bacterial peritonitis
Abdominal pain or tenderness, fever, nausea/vomiting, diarrhoea, GI bleed
Diagnostic paracentesis should be performed in all hospitalised patients with cirrhosis and ascites. An absolute peritoneal fluid neutrophil count (ANC) >250 cells/mm^3 is the accepted criterion for the diagnosis for spontaneous bacterial peritonitis.

Hepatic steatosis

Alcoholic liver disease
No specific differentiating signs or symptoms.Quantification of alcohol intake. Most studies have used a cut-off point of 40 g of alcohol per week to exclude non-alcoholic fatty liver disease (NAFLD).
AST:ALT ratio (AAR) typically 2:1 in alcohol liver disease.
Cryptogenic cirrhosis
No specific differentiating signs or symptoms.
Diagnosed by exclusion of all other forms of chronic liver disease and histology, which is non-diagnostic for any particular disease entity. Circumstantial evidence indicates that NAFLD and non-alcoholic steatohepatitis (NASH) is the likely aetiology in a significant number of patients labelled with cryptogenic cirrhosis - that is, burned-out NASH. [40] Other causes of cryptogenic cirrhosis include undiagnosed or burned-out autoimmune hepatitis, 'unknown' viral (non-A, non-B, non-C) hepatitis, and occult alcoholism.
Autoimmune hepatitis
No specific differentiating signs or symptoms.
Circulating autoantibodies, hyperglobulinaemia, and inflammatory changes on liver histology.
Hepatitis B
High-risk behaviour (unprotected sex with multiple partners, intravenous drug use, tattoos), blood transfusions prior to 1992, needlestick injury, or from endemic areas (Asia, Africa, Middle East, Eastern Europe, Amazon, Alaska). No specific differentiating signs or symptoms.
HBsAg, HBsAb, HBcAb, HBeAg, HBeAb, and HBV DNA may be positive.
Hepatitis C
High-risk behaviour (unprotected sex with multiple partners, intravenous drug use, tattoos), blood transfusions prior to 1992, needlestick injury, or from endemic areas (Asia, Africa, Middle-East, Eastern Europe, Amazon, Alaska). No specific differentiating signs or symptoms.
HCV Ab, HCV PCR may be positive.
Haemochromatosis (HFE)
Usually presents in midlife. Symptoms include fatigue, joint pains, new-onset diabetes, decreased libido, cardiac arrhythmias, and heart failure.
Iron studies indicate elevated ferritin and percent iron saturation, HFE genetic testing is positive, and iron quantification on histology is elevated.
Primary biliary cirrhosis
Women comprise 75% to 90% of patients with the disease. Most common presenting symptoms are fatigue, pruritus, and abdominal pain.
Significant elevations in alkaline phosphatase, gamma-glutamyl transpeptidase, and immunoglobulin levels (mainly IgM) are usually the most prominent findings. A positive anti-mitochondrial antibody is found in 90% to 95% of patients and has a specificity of 98%. [41]
Primary sclerosing cholangitis
A chronic liver disease caused by progressive inflammation and scarring of the bile ducts of the liver. Associated with inflammatory bowel disease (namely, ulcerative colitis) in 70% of cases.
Cholangiogram (ERCP or MRCP); elevated alkaline phosphatase and gamma-glutamyl transpeptidase; 80% of patients will have positive peripheral anti-neutrophilic cytoplasmic antibody.
Wilson's disease
Autosomal-recessive genetic disorder in which copper accumulates in tissues; results in neurological or psychiatric symptoms and liver disease. Wilson's disease manifests as liver disease in children and adolescents, peaking at ages 10 to 13 years, and as neuropsychiatric illness in young adults aged 19 to 20 years. Characterised by presence of Kayser-Fleischer rings on slit-lamp examination.
Diagnosis is confirmed by low serum ceruloplasmin, elevated urinary copper excretion, and elevated hepatic copper content.One of the few chronic liver diseases that can present as acute liver failure.
Alpha-1 antitrypsin (A1AT) deficiency
A genetic disorder caused by defective production of A1AT, leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells. Most commonly presents as neonatal jaundice.
The diagnosis is confirmed by liver biopsy, which shows eosinophilic, periodic acid Schiff-positive, diastase-resistant globules in the endoplasmic reticulum (ER), or periportal hepatocytes.
Drug-induced liver injury
Often idiosyncratic. History of increase in aminotransferases after starting medication, which normalises after discontinuation.
Peripheral eosinophilia in some cases; histology is sometimes helpful.

Hepatitis A

Acute hepatitis B
Clinical features of viral hepatitis in a person with a history of injection drug use, nasal snorting of drugs, multiple sexual partners, or transfusion of blood products before donors were routinely screened. Disease incubation period is longer.
Anti-HAV IgM is negative, whereas hepatitis B surface antigen and/or IgM antibody to hepatitis B core antigen are positive.
Hepatitis E
Clinical features of viral hepatitis in a person with a history of recent travel to endemic areas or exposure to an infected person or contaminated water. Hepatitis E is often more severe and fulminant in pregnant women.
Test for anti-hepatitis E virus IgM in acute-phase sera.
Acute hepatitis C
Clinical features of viral hepatitis in men who have sex with men, or in people with a history of injection drug use, positive HIV status, an occupational exposure in the previous 6 months, or blood transfusion before donors were routinely screened.
Anti-hepatitis C virus (HCV) positive by ELISA and confirmed by recombinant immunoblot assay (RIBA) or positive HCV RNA.Anti-HCV may be negative in acute HCV infection; thus, patient is tested for HCV RNA if anti-HCV is negative, the patient has HCV-associated risk factors, and acute HCV infection is suspected.
Epstein-Barr virus infection
Clinical features of viral hepatitis with no hx of exposure to other organisms that can cause hepatitis; classically display lymphadenopathy and splenomegaly in EBV infection.
Negative serology results for all types of viral hepatitis. Atypical lymphocytes tend to be present. EBV IgM and IgG positive.
Coxsackie virus
Classically displays buccal or pharyngeal lesions with Coxsackie virus infection.
Hand-foot-and-mouth disease mainly is a clinical diagnosis. Coxsackie serology can be helpful if available. Atypical lymphocytes tend to be present.
Cytomegalovirus infection
Clinical features of viral hepatitis with no hx of exposure to other organisms that can cause hepatitis.
Negative serology results for all types of viral hepatitis. Atypical lymphocytes tend to be present. CMV IgM and IgG positive. CMV PCR in blood positive.
Herpes simplex virus infection
Clinical features of viral hepatitis with no hx of exposure to other organisms that can cause hepatitis; may display characteristic cutaneous ulceration.
Negative serology results for all types of viral hepatitis. Mainly a clinical diagnosis (aided by presence of typical muco-cutaneous lesions). A liver biopsy confirms diagnosis.
Biliary atresia
Typical presentation is with jaundice between birth and 6 to 8 weeks of age. Biliary atresia is very unlikely if a child is over 8 weeks old at the onset of jaundice.
Negative serological markers for other causes of acute hepatitis. Alk phos generally more than 3 times the ALT or AST levels. Endoscopic retrograde cholangiopancreatogram may be needed, especially if bile ducts are dilated on ultrasound.
Auto-immune hepatitis
Ninety percent of cases occur in women. Other auto-immune disorders may be present; 25% to 40% of cases can present with acute hepatitis. HAV has been described as a possible trigger for auto-immune hepatitis. [38] [39]
ESR elevated.Serum electrophoresis and serum autoantibodies: patients may have serum gamma-globulin concentrations more than twice normal, and sometimes antinuclear antibodies and/or anti-smooth muscle (anti-actin) antibodies. Patients with another subtype may have normal or only slightly elevated serum gamma-globulin concentrations, but will have antibodies against a particular cytochrome p450 isoenzyme that are called anti-LKM (liver kidney microsome).Liver biopsy is characterised by a periportal lesion or interface hepatitis (a portal mononuclear and plasma cell infiltrate).
Alpha-1 antitrypsin disease
Uncommonly presents as acute hepatitis.
Alpha-1 antitrypsin serum level reduced; phenotyping demonstrating characteristic alpha-1 antitrypsin-variant proteins. Liver biopsy stain for periodic acid-Schiff-positive inclusions.
Alcoholic hepatitis
History of excessive alcohol consumption.Hepatomegaly and jaundice are found in approximately 95% and 55% of persons presenting with alcoholic hepatitis, respectively.
AST/ALT ratio of at least 2:1 in up to 80% of cases. Anaemia is present in 50% to 70% and leukopenia and thrombocytopenia present in 10% to 15%. [40]
Ischaemic hepatitis
Also referred to as “shock liver.” History of injury or hypotension, postoperative patient.
Negative viral hepatitis serologies.
Drug-induced hepatitis
History of excessive paracetamol ingestion or therapeutic amounts of paracetamol in a patient with alcoholic liver disease or alcohol ingestion; other therapeutic drugs may cause hepatitis (e.g., isoniazid, non-steroidal anti-inflammatory drugs, beta-lactam antibiotics, sulpha-containing compounds, insulin-sensitising drugs); may affect men and women of all ages but more common in women and the elderly.
History of drug consumption; improvement usually occurs with discontinuation.
Wilson's disease
Rarely presents after age 40 years without neuropsychiatric symptoms; rarely presents as acute hepatitis.Kayser-Fleischer rings upon slit-lamp ophthalmological examination.View image
24-hour urine for copper >100 micrograms, and serum ceruloplasmin <180 mg/L (18 mg/dL) is positive for Wilson's disease. Liver biopsy and assay of copper >250 micrograms/g dry weight indicates Wilson's disease. A liver copper level of <150 micrograms/g dry weight rules out Wilson's disease.

Hepatitis B

Acute hepatitis A virus (HAV) infection
There may be no differences in signs and symptoms.
Serum laboratory test will be positive for HAV-IgM antibody.
Acute hepatitis C virus (HCV) infection
There may be no differences in signs and symptoms.
Serum laboratory test will be positive for HCV antibody, and RNA-PCR will be positive for hepatitis C. Typically, symptomatic acute HCV patients will show very high ALT, AST, and bilirubin.
Chronic HCV infection
There may be no differences in signs and symptoms.
Patients may have normal or elevated LFTs with positive serum HCV antibody and HCV RNA-PCR.
Hepatitis D virus (HDV) co-infection with HBV
There may be no differences in signs and symptoms. Patient may have sudden rise in hepatic panel.
Serum hepatitis D RNA and hepatitis D IgM antibody will be positive.
Acute hepatitis E virus (HEV) infection
Symptoms and signs can be identical to other acute viral hepatitis. It is most common in pregnant women in developing countries with a hot climate.
Serum HEV antibody (IgM) will be positive, including serum HEV RNA-PCR.
Cytomegalovirus (CMV) hepatitis
May have history of immunocompromise including organ transplant.
Positive serum CMV-IgM antibody and CMV DNA PCR.
Epstein Barr virus (EBV) hepatitis
Patients typically can experience fever, fatigue, pharyngitis, malaise, myalgia, and lymphadenopathy (particularly posterior cervical chain).
Positive Monospot test and serum heterophile antibody. Serum EBV-IgM antibody and EBV DNA-PCR are positive.
Herpes Simplex virus (HSV) hepatitis
Patient may be immunosuppressed or pregnant but can also be immunocompetent. Patients may present as acute viral hepatitis with or without liver failure.
Serum HSV IgM antibody and HSV DNA-PCR are positive.
Acute alcoholic hepatitis
There may be no differences in signs and symptoms. History of moderate or heavy alcohol use.
Negative serological tests for viral hepatitis. AST level is higher than ALT, with elevated gamma glutamyl transferase. Liver biopsy may show steatosis, ballooning hepatocytes, Mallory hyaline, lobular neutrophilic infiltration, with or without pericellular fibrosis.
Drug- or toxin-induced hepatitis
There may be no differences in signs and symptoms. There may be a history of exposure to hepatotoxic drugs or toxins.
Liver biopsy may show the features of hepatocellular, cholestatic, or mixed pattern of injury, including cholestasis.
Autoimmune hepatitis
There may be no differences in signs and symptoms.
There may be increased levels of serum globulin, antinuclear antibody, antismooth muscle antibody, liver/kidney microsomal antibodies, and/or antibodies against soluble liver antigen/liver pancreas antigen. Liver histology may show interface hepatitis with plasma cell infiltrates.
Biliary obstruction
Symptoms associated with biliary obstruction may include RUQ pain, fever/chills, jaundice, pruritus, nausea, and vomiting.
Ultrasound, CT scan, or MRI cholangiography may show dilatation of biliary tract. In case of malignant obstruction, a mass may be seen in the liver.
Metastatic liver diseases
Patients may be asymptomatic or have symptoms and signs of malignancy of other primary sites, including biliary obstructive features.
CT scan or MRI of abdomen may show one or more metastatic masses in the liver
Acute ischaemic hepatitis
Patients may have symptoms of ischaemia such as acute heart failure, shock, or sepsis.
ECG may show features of myocardial ischaemia or infarction. CXR and echocardiogram may show features of congestive heart failure. Doppler ultrasound of liver may show portal vein thrombosis or acute occlusion of hepatic artery.
Budd-Chiari syndrome
There may be no differences in signs and symptoms.
Doppler ultrasound may show hepatic vein thrombosis or inferior vena caval thrombosis.
Acute fatty liver of pregnancy
Pregnant patient may present with jaundice.
Diagnosis of exclusion of other diseases with characteristic symptoms and signs in pregnant patients.
Wilson's disease
There may be no differences in signs and symptoms.
Increased urinary copper, decreased serum ceruloplasmin, and Kayser-Fleischer rings on slit lamp eye examination.
Haemochromatosis
There may be no differences in signs and symptoms.
High iron saturation (>45% transferrin saturation) and haemochromatosis gene mutations. Liver biopsy shows iron deposition in hepatocytes.

Hepatitis C

Chronic hepatitis B
There may be no differentiating signs or symptoms.
Hepatitis B surface antigen test is positive.Hepatitis C antibody test is negative.
Alcoholic liver disease
There may be symptoms of alcohol dependency, but these are not diagnostic.
Hepatitis C antibody test is negative.
Steatohepatitis
There may be no differentiating signs or symptoms.
Ultrasound may show fatty liver.Hepatitis C antibody test is negative.Liver biopsy shows steatohepatitis.
Haemochromatosis
There may be no differentiating signs or symptoms, but some patients with advanced disease may also have features of cardiomyopathy, arthritis, or diabetes.
Iron indices are abnormal (but a caution is that patients with advanced liver disease of any aetiology, particularly those with cirrhosis, may have very elevated ferritin and transferrin saturations). A genetic test for the haemochromatosis gene (C282Y mutation) may be helpful to differentiate.
Other chronic liver diseases
Patients may have a history or physical findings suggestive of metabolic, auto-immune, or drug-induced liver disease.
Hepatitis C antibody test is negative.Blood chemistries or serologies, toxicology screen, or liver biopsy may confirm an alternate diagnosis.

Hepatoma

Cholangiocarcinoma
Progressive obstructive jaundice, pruritus, clay-coloured stools, and dull pain in RUQ in late stage.
Transaminases, PT/INR, and alpha fetoprotein (AFP) are usually normal or mildly elevated. Patients typically have an elevated bilirubin, an elevated alkaline phosphatase, and an elevated gamma-glutamyl transferase.CA 19-9 may be elevated.There may be dilated bile ducts on ultrasound or CT scan of the abdomen.Endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) is very helpful in diagnosis.
Hepatic adenoma
These patients usually are asymptomatic but rarely may present with acute abdominal pain, RUQ tenderness, and shock due to haemoperitoneum.
On ultrasound or CT scan of the abdomen, the adenoma appears as subcapsular hypo-echoic lesion and is very well circumscribed. Doppler blood flow shows venous pattern instead of arterial hypervascularisation pattern of hepatoma.Patients generally have a normal AFP.
Haemangioma of liver
Typically asymptomatic. Acute abdominal pain can result from thrombosis or bleeding within the haemangioma due to the stretching and inflammation of the Glisson capsule of the liver. Patients do not have any coexistent chronic liver disease.
Normal LFTs and normal AFP.The majority of hepatic haemangiomas are well demarcated, smooth, and hypodense with a homogeneous appearance on ultrasound, CT scan, or MRI of the abdomen. MRI is very sensitive and specific for this disease.
Fibrolamellar hepatocellular carcinoma
Patients may present with abdominal pain and/or palpable mass in the abdomen. It is not associated with chronic liver disease, cirrhosis, or hepatotoxins.
LFTs and AFP are usually normal or slightly elevated.Typical stellate central scar is the finding on CT scan or MRI of the abdomen. However, CT scan of the abdomen is the preferred test for diagnosis, staging, and postoperative follow-up. There may be regional lymph node involvement in 50% to 70% of cases due to aggressiveness of the tumour.Typical liver histology includes pattern of nests, sheets, or cords of malignant cells separated by lamellar bands of dense, hypocellular, and collagen connective tissue.
Focal nodular hyperplasia (FNH)
One third of patients may have abdominal discomfort or palpable liver mass.There is no history of chronic liver disease in patients with FNH.
LFTs and AFP are within normal range in these patients.Presence of central scar on ultrasound, CT scan, MRI scan, or technetium sulphur colloid scanning of abdomen is very diagnostic.There is no requirement of tissue diagnosis to confirm FNH.
Metastatic liver disease
Patients may have signs and symptoms of primary cancer, but in many cases are diagnosed at the time of liver metastasis. The liver may be the site of metastasis from virtually any primary malignant neoplasm, but the most common primary sites are colon, stomach, pancreas, breast, lung, neuro-endocrine tumours, and eye.
The contrast-enhanced CT of the abdomen is very sensitive (80% to 90%) and specific (99%) in differentiating metastatic liver cancer from hepatoma. Gadolinium-enhanced MRI scan, PET scan, and CT arteriography of the abdomen are very helpful in diagnosing liver metastatic disease, but they are not required.
Hepatic cyst
Cysts are usually incidental findings; they do not cause any symptoms until they become enlarged (>5-6 cm). There is no association with chronic liver diseases or viral hepatitis leading to liver cysts.
On ultrasound or CT scan of the abdomen, simple cysts appear as thin wall cysts. Hydatid cysts usually have daughter cysts. Polycystic liver-disease patients have multiple cysts. Unlike hepatoma, cystadenoma or cystadenocarcinoma does not usually have any calcification, and these cysts usually have internal septations.
Epithelioid haemangioendothelioma
Symptoms are non-specific, including weight loss or RUQ discomfort. There is no association with chronic liver disease.
LFTs are normal unless patients have advanced disease.Doppler ultrasound or CT of the abdomen shows vascular lesion.Histology is diagnostic and usually positive for endothelial markers factor VIIIR:Ag (vWF), CD34, and CD31.
Liver abscess
Associated with fever and RUQ tenderness, which is acute in onset. There is no association with chronic liver disease.
Air-fluid levels can be seen on imaging studies.Patients usually have normal AFP.Cultures are diagnostic but can be normal.

Hepatorenal syndrome

Pre-renal azotaemia
History of GI haemorrhage, intense diarrhoea, aggressive diuretic therapy, or excessive paracentesis.
Therapeutic trial of intravenous fluid results in improvement in renal function.
Acute tubular necrosis - ischaemic
Underlying condition that causes hypotension, such as prolonged pre-renal azotaemia, hypovolaemia resulting in hypotension, or sepsis; or ischaemia due to vascular disease.
Sodium <10 mmol/L (<10 mEq/L); urine osmolarity > plasma osmolarity; protein <500 mg/dL.
Acute tubular necrosis - nephrotoxic
History of recent use of nephrotoxic agents such as gentamicin or NSAIDs, or exposure to radiocontrast agents.
Urine sodium generally >40 mmol/L (40 mEq/L).
Obstructive renal nephropathy
Symptoms depend on cause.Acute obstruction, such as renal calculi or acute papillary necrosis, presents with severe pain and haematuria.Chronic obstruction, such as prostatic hypertrophy, may be asymptomatic.
Renal ultrasonography shows hydronephrosis and hydroureter.
Glomerulonephritis
Particularly in the setting of cirrhosis due to hepatitis B or C.
Proteinuria (>500 mg/dL).RBC and red cell casts in urine.May have cryoglobulinaemia if viral hepatitis.Renal biopsy changes consistent with glomerulonephritis.

Hereditary spherocytosis

Non-haemolytic anaemia
No specific differentiating clinical features, but jaundice and splenomegaly indicate haemolysis rather than other causes of anaemia.There is more likely to be a FHx of HS in patients with HS.
The FBC and blood smear appearances are typical for each type of anaemia and do not typically have the same appearance as HS (i.e., normal or reduced Hb, increased reticulocytes and spherocytes on the blood smear).Iron deficiency anaemia (most common cause of anaemia): FBC and blood smear reveal a microcytic (low MCV), hypochromic (increased central pallor) anaemia; if performed, serum ferritin is low.
Other causes of haemolytic anaemia
May be no specific differentiating clinical features.There is more likely to be a FHx of HS in patients with HS.
FBC and blood smear help to confirm specific diagnosis.Spherocytes may not be present on the blood smear. Schistocytes are indicative of a microangiopathic process (e.g., DIC, TTP, haemolytic uraemic syndrome) or a traumatic process (e.g., mechanical prosthetic heart valve, march haemolysis). Elliptocytes may indicate elliptocytosis. Blister or bite cells indicate the presence of oxidant damage to the cell. Spur cells may occur with liver disease. RBC inclusions may occur with infections (e.g., malaria, babesiosis, and Bartonella infections).The direct anti-globulin test (DAT) is usually positive in auto-immune haemolytic anaemia. A negative DAT makes auto-immune haemolysis very unlikely.Hb electrophoresis detects haemoglobinopathy.Glucose-6-phosphate dehydrogenase deficiency is diagnosed by fluorescent spot test, followed by definitive assay of glucose-6-phosphate dehydrogenase activity by spectrophotometry tests.Flow cytometry for CD55/CD59 tests for paroxysmal nocturnal haemoglobinuria.There is abnormal renal function with haemolytic uraemic syndrome or TTP.
Other causes of spherocytosis
There is more likely to be a FHx of HS in patients with HS.
Blood smear may reveal morphology that is atypical for HS. Further specialist investigation may be required for atypical cases (e.g., quantitative protein analysis by sodium dodecyl sulphate-polyacrylamide gel electrophoresis). [13]The eosin-5-maleimide binding test may be abnormal in other red-cell disorders, particularly congenital dyserythropoietic anaemia type II .Maternal screen and a positive DAT in an infant detects irregular maternal antibody as a cause of neonatal spherocytosis.
Other red-cell membrane disorders
May be no specific differentiating clinical features.There is more likely to be a FHx of HS in patients with HS.
Careful examination of the blood smear for morphology of red cells is important. Further specialist investigation may be required for atypical cases. [13]
Other causes of jaundice
May be no specific differentiating clinical features.There is more likely to be a FHx of HS in patients with HS.
Abnormal liver function tests (LFTs) (various different patterns of specific liver enzyme abnormality depending on the condition) are an indicator of liver dysfunction. LFTs will usually be normal in HS apart from elevated unconjugated bilirubin.Screening for infectious hepatitis will be positive if this is the cause of jaundice, but negative in HS. However, HS can present during an exacerbation due to intercurrent infection (e.g., infectious mononucleosis), which may be associated with deranged LFTs.Neonatal blood smears can be difficult to interpret and the osmotic fragility may be normal, even with HS. Review of the blood smear after a period of time may be needed before a definite diagnosis is made. The typical smear appearances of spherocytes in HS are easier to see after a few months.

Herpes simplex infection

Syphilis
Characterised by a single non-tender ulcer as opposed to a painful ulcer.
A positive non-treponemal test: for example, rapid plasma reagin/Venereal Disease Research Laboratories titre or darkfield microscopy result.
Chancroid
Characterised by a single deep ulcer, which is painful, as opposed to multiple painful ulcers with herpes.
The presence of Haemophilus ducreyi on culture or PCR differentiates.
Lymphogranuloma venereum
There is a lack of vesicles, with single or few ulcers and unilateral lymphadenopathy.
A positive chlamydia trachomatis culture and genotyping for serovars L1 to L3 help differentiate.
Contact dermatitis
No differentiating signs and symptoms.
Negative for HSV testing.
Behçet's disease
Oral, eye, genital involvement. Patients with Behcet’s may also have oral ulcers and uveitis.
Negative for HSV testing.
Rheumatological disease
Exclusive oral involvement more likely.
Elevated ESR and/or positive rheumatic factor titre, ANA titre.
Crohn's disease
Exclusive oral involvement more likely in addition to GI symptoms presence.
Evidence on colonoscopy.
Ulcerative colitis
Exclusive oral involvement more likely.
Positive for ANA and evidence on colonoscopy.
Scabies
May have disseminated skin involvement.
Skin scraping for mites.
Fixed drug eruption
History of medicine use.
No differentiating test is available.
Squamous cell carcinoma
Non-healing ulcerative lesions present.
Skin biopsy reveals carcinoma.
Shingles on buttocks or lower extremities, or periorally
Vesicles or pustules on an erythematous base present in both shingles and genital herpes. However, shingles typically erupts in a dermatomal distribution, with multiple lesions found over a wide distribution in a single dermatome, without extension over the midline.
PCR of vesicular or pustular fluid for varcella-zoster.

Herpes zoster infection

Contact dermatitis
Presents as a localised rash or irritation of the skin caused by contact with a foreign substance. The pain and the rash usually occur simultaneously.
Eliminating exposure to the irritating agent usually results in symptom resolution.
Cholecystitis
Presents with pain in the right upper quadrant of the abdomen, accompanied with nausea, vomiting, and fever. On examination patients may have Murphy's sign.
Patients have elevated levels of alkaline phosphatase, bilirubin, C-reactive protein, and WBCs. Ultrasound or CT scan may show a bile duct blockage, gallstones, and inflammation of the gallbladder.
Ulcerative keratitis
Symptoms depend on the cause. Presents with pain and redness in the affected eye, with visual changes dependent on the ulcer location. Some may also present with purulent discharge. The distinctive feature that differentiates HZ from other causes is the development of rash in the affected dermatome.
Fluorescein staining would show the presence of a dendritic ulcer if the cause is herpes simplex virus and is unrelated to HZ.A slit-lamp examination would indicate other causes of ulcerative keratitis, such as a foreign body.
Glaucoma, acute angle-closure
Presents with periorbital pain, blurred vision, and headache. However, there is no development of an accompanying rash in the dermatome innervated by the eye.
Tonometry shows increased intraocular pressure (>20 mmHg), diagnostic of glaucoma.
Trigeminal neuralgia
Presents with an intense, stabbing, electric shock-like pain in the areas of the face innervated by the trigeminal nerve. Patient may locate a trigger area for the pain. Patients do not develop a rash.
No differentiating test is available.
Appendicitis, acute
Typically presents with pain in the right lower abdominal quadrant. Additionally presents with nausea, vomiting, and sometimes signs of bowel obstruction, which are not present in patients with HZ. There is no accompanying rash with these symptoms.
On FBC, WBCs are often elevated. CT scan would indicate inflammation of the appendix.
Renal calculi
Presents with severe colicky pain and inability to lie still. Other symptoms include urinary frequency, blood in urine, and painful urination. Flank pain shows on examination. These symptoms are not accompanied by the development of a rash.
A kidney, ureter, and bladder x-ray would show the location of the calculi.

Hiatal hernia

Angina pectoris
Angina pectoris is brought on by exertion. Chest pain from para-oesophageal hernia is usually related to eating or drinking.
Cardiac exercise testing: stress test may be positive.
GORD
May be unable to distinguish between GORD and hiatal hernia on clinical findings.
Upper GI series: : may show oesophagitis (erosion, ulcerations, strictures) or Barrett's oesophagus; hiatal hernia absent.
Pneumonia
With pneumonia, the patient may have fever, productive cough, pleurisy, and shortness of breath.
A CXR will demonstrate a pulmonary infiltrate.
Gastric outlet obstruction
The patient may have vomiting of undigested food.
An upper GI series, abdominal CT scan, or both will demonstrate obstruction at the level of the pylorus.
Oesophageal motility disorder
Oesophageal motility disorders are difficult to diagnose based on symptomatology alone.
An upper GI series may indicate gross oesophageal dysmotility.Manometry can provide precise measurements by which various motility disorders may be ruled in or ruled out.
Gastric atonia
Gastric atonia is difficult to diagnose based on symptomatology alone.
An upper GI series will rule out hiatal hernia and may indicate gastric atonia. A nuclear gastric emptying study is useful for diagnosis of atonia, by showing a delay or absence of gastric emptying after ingestion of the nuclear tracer.

Hiccups

Gasping
A convulsive or laborious respiration with an abnormal breathing pattern characterised by shallow, slow (3 to 4 per minute), and irregular inspirations followed by irregular pauses. The distinctive 'hic' noise produced by closure of the glottis in hiccups is absent.
Clinical diagnosis with no differentiating tests.
Burping
A noisy expulsion of gas from the stomach through the mouth with absence of the involuntary inspiration observed in hiccups.
Clinical diagnosis with no differentiating tests.

Hidradenitis suppurativa

Acne vulgaris
Typically occurs on the face, chest, and back. Morphology of lesions can be indistinguishable from HS lesions. However, acne vulgaris rarely results in draining sinus tracts. [1]
No distinguishing tests.
Crohn's disease
Fistulas and sinus tracts are usually perianal in distribution. Patients may experience gastrointestinal symptoms, such as bloody diarrhoea, abdominal cramps, and lower abdominal pain. [1]
Endoscopy and biopsy will show inflammation with disruption of crypt architecture; non-caseating granulomas may be present.The presence of granulomas on skin biopsy is suggestive but not diagnostic of cutaneous Crohn's disease.
Psoriasis, inverse type
Lesions are usually macerated red patches rather than discrete abscesses or nodules. [1]
Skin biopsy may demonstrate classic findings of psoriasis: regular acanthosis, parakeratosis, and hypogranulosis.
Epidermal inclusion cyst
Typically presents as a solitary lesion, which usually has a visible punctum at the surface. Inflammation is common. [1]
Excisional biopsy is diagnostic and therapeutic.
Furunculosis
Presents as a solitary abscess often with a collarette of fine scale that is caused by Staphylococcus species. More often presents after abrasion of the skin or in immunocompromised patients. [1]
Bacterial culture will demonstrate pathogenic bacteria, often MRSA.
Lymphogranuloma venereum
Sexually transmitted disease caused by Chlamydia trachomatis. Typically presents as a suppurative inguinal adenitis with pronounced lymphadenopathy that shows a characteristic groove sign. [1]
Complement fixation test will show a titre >1:64 or a 4-fold rise between acute and convalescent specimens. However, a complement fixation with a high titre in the absence of symptoms does not confirm lymphogranuloma venereum, and a low titre does not exclude it.
Squamous cell carcinoma
Usually ulcerated. May be a complication of HS.
Skin biopsy will show evidence of malignancy with foci of keratinisation and formation of squamous whorls, where the neoplastic cells tightly wrap around each other.

Hip fractures

Acetabular fracture
Leg is rarely shortened or externally rotated.
Plain x-ray demonstrates acetabular fracture.
Pubic rami fracture
Leg is rarely shortened or externally rotated.
Plain x-ray demonstrates pubic rami fractures.If x-ray is negative, MRI will demonstrate pubic rami fractures.
Femoral shaft or sub-trochanteric femur fracture
Often thigh is deformed.
Plain x-ray demonstrates femoral shaft or sub-trochanteric fracture.
Femoral head fracture
Often associated with hip dislocation.
Plain x-ray and pelvic CT demonstrates femoral head fracture.
Septic hip
Fever and chills.
Hip aspiration may reveal frank pus or a turbid fluid suggestive of infection.Laboratory isolation of infecting organisms in the fluid is confirmatory.Elevated WBC count.

Hirschsprung's disease

Meconium-plug syndrome
The expulsion of a plug of meconium with resolution of symptoms and the absence of other signs characteristic of Hirschsprung's disease help establish the diagnosis.
Contrast enema can be both diagnostic and therapeutic.Air mixed with meconium show up as a soap bubble or calcification-like appearance on radiographs.
Cystic fibrosis (meconium ileus)
Manifested by a clinical picture consistent with intestinal obstruction, with the child frequently exhibiting respiratory symptoms.A family history of cystic fibrosis may be noted.
The absence of air-fluid levels in an upright abdominal film and the ground-glass appearance of the lower abdomen are characteristic radiographic signs.
Small left colon syndrome
Symptoms usually improve following contrast enema and resolve after several weeks.The mother is frequently diabetic.
Contrast enema demonstrates a rather narrow left colon to the level of the splenic flexure.
Hypothyroidism
Colonic ileus and abdominal distension.The abdominal distension will accompany bradycardia, disinterest in eating, and other signs associated with hypothyroidism.
TSH is elevated in primary hypothyroidism.
Cerebral injury
Colonic ileus and abdominal distension.A history of birth trauma can make one suspicious of this cause of ileus.
Diagnosis is clinical.
Chronic constipation
The proximal colon is huge and full of inspissated faecal material.Children usually become symptomatic after the sixth month of life; they neither vomit nor become seriously ill.Patients have overflow incontinence or encopresis, a constant, chronic soiling without evidence of neuromuscular disturbance.The rectum is impacted with stool.
Rectal examination in these children reveals a severe faecal impaction just above the anal canal.Contrast enema shows a reverse pattern of dilation. In idiopathic constipation, the rectosigmoid is enormous and the proximal colon is normal caliber.
Distal small bowel atresia or stenosis
Abdominal distension and bilious vomiting.
Plain x-ray often shows evidence of an intestinal atresia.Contrast enema will show a microcolon.

Histiocytosis

Seborrhoeic dermatitis
No differentiating signs and symptoms from Langerhans cell histiocytosis (LCH) with skin involvement, especially in newborns.
Tissue biopsy: negative for CD1a and langerin (CD207).
Juvenile xanthogranuloma (JXG)
Can mimic LCH very closely in a number of tissue sites (especially the skin), and sometimes can be multi-systemic.Dermal JXG can be seen in children after LCH. [59]
Tissue biopsy: negative for CD1a and S100; positive for factor XIIIa, fascin, CD68, CD163, and CD14.
Rosai-Dorfman disease (RDD)
Also called sinus histiocytosis with massive lymphadenopathy.Most patients present with bilateral painless cervical lymphadenopathy with fever, night sweats, and weight loss.Extranodal disease occurs in 40% of patients, with skin, lung, liver, CNS, and bone being most commonly involved. [60]Bone RDD may mimic the lesions of healing and involuting LCH. Coexistence of LCH and RDD has been reported. [61]
White blood cell count: leukocytosis.Serum electrophoresis: hypergammaglobulinaemia.Tissue biopsy: positive for S100, fascin, CD68, and CD163; intracytoplasmic emperipolesis of lymphocytes, neutrophils, and plasma cells is common.
Osteomyelitis
Difficult to distinguish clinically from LCH with bone involvement.Chronic multifocal osteomyelitis can be confused with multifocal bone disease and may have few or no constitutional symptoms.
Tissue biopsy: negative for CD1a and langerin (CD207).Cultures from biopsy sample: positive for bacteria or atypical mycobacteria.
Ewing's sarcoma
Difficult to distinguish clinically from LCH with bone involvement.
Tissue biopsy: negative for CD1a and langerin (CD207).X-ray: aggressive radiological features such as significant periosteal reaction, poorly defined borders, and onion-skinning are typical. With healing LCH lesions, there is re-calcification and development of a well-defined sclerotic rim.
Osteosarcoma
Difficult to distinguish clinically from LCH with bone involvement.
Tissue biopsy: negative for CD1a and langerin (CD207).X-ray: with healing LCH lesions, there is re-calcification and development of a well-defined sclerotic rim.
Tuberculosis
Disseminated tuberculosis may mimic multi-system disease.Progressive fever and weight loss are usually present.
Sputum smear: positive for acid-fast bacilli.Sputum culture: positive.Tuberculin skin testing: millimetres of induration.Chest x-ray: normal; abnormal typical for TB; abnormal atypical for TB.Tissue biopsy: caseating granulomas typically seen.
Acute lymphoblastic leukemia (ALL)
Can be confused with multi-system disease in the presence of hepatosplenomegaly, lymphadenopathy, fever, pallor, and petechial rash.
Bone marrow aspirate and biopsy: bone marrow hypercellularity and infiltration by lymphoblasts.Peripheral blood smear: leukemic lymphoblasts with or without hyperleukocytosis.Serum electrolytes: hyperuricaemia, hyperkalaemia, hyperphosphataemia.
Acute myelogenous leukemia (AML)
Neonatal acute monoblastic leukemia can present with skin rash that can mimic LCH with skin involvement.
Bone marrow aspirate and biopsy: bone marrow hypercellularity and infiltration by myeloblasts.Peripheral blood smear: myeloblasts, hyperleukocytosis, or pancytopenia.
Non-Hodgkin's lymphoma (NHL)
Can be difficult to differentiate from LCH in the presence of lymphadenopathy and systemic symptoms.
Tissue biopsy: negative for CD1a and langerin (CD207) and positive for T- or B-cell markers.
Pituitary adenoma
Can also cause central diabetes insipidus.No history of skin rash, bone pain, or recurrent otitis.
CT/MRI pituitary with contrast: sellar mass.
Craniopharyngioma
Can also cause central diabetes insipidus.No history of skin rash, bone pain, or recurrent otitis.Macrocephaly and hydrocephalus.
MRI brain with contrast: variable; T1 signal (T1 hyperintensity secondary to high protein content in cystic component); mixed solid and cystic components with enhancement of the solid component and cyst wall; T2 and fluid attenuation inversion recovery (FLAIR) show heterogeneous signal in the solid components and cyst hyper-intensity; calcification has low signal on T2.Biopsy and histology: adamantinous/squamous epithelial tumour; calcification.

Histoplasmosis

Community-acquired pneumonia
Cough, fever, and pleuritic chest pain are usually of a shorter duration than in histoplasmosis pneumonia.
Chest x-ray with lobar consolidation for typical or bilateral interstitial infiltrates for atypical pneumonia.Hilar lymphadenopathy is not seen.Sputum Gram stain and culture with many neutrophils and bacteria other than normal oral flora.Good response to appropriate antibiotic therapy.
Pneumocystis jiroveci pneumonia (PCP)
Patients with advanced HIV/AIDS with Pneumocystis jiroveci pneumonia present with fevers and night sweats that may be indistinguishable from features of pulmonary histoplasmosis.
Sputum staining with methenamine silver ('silver stain') demonstrating round or crescent-shaped cysts typical of P jiroveci. Elevated serum LDH >3.64 microkat/L (>220 units/L). Although elevated levels of LDH are a non-specific finding, rising levels despite adequate therapy are a marker for poor prognosis in patients with PCP. Chest x-ray shows diffuse bilateral interstitial pulmonary infiltrates.
Pulmonary tuberculosis
Presents with symptoms that can be difficult to differentiate clinically from acute and chronic histoplasmosis pneumonia.
Sputum smears demonstrating the presence of acid-fast bacilli. Sputum cultures growing Mycobacterium tuberculosis. PPD skin test with ≥15 mm induration.
Sarcoidosis
Autoimmune disorder characterised by non-caseating granulomas of various organs and multi-system involvement including erythema nodosum, polyarthritis, uveitis, cranial neuropathy, and other features.
Chest x-ray shows hilar and/or paratracheal adenopathy with upper lobe predominant, bilateral infiltrates, pleural effusions (rare), and egg shell calcifications (very rare).Elevated serum ACE level >40 micrograms/L.
Non-small-cell lung cancer
Symptoms include cough, haemoptysis, chest pain, and/or dyspnoea.
Sputum cytology showing malignant cells. Chest CT scan will show pulmonary nodules or hilar lymphadenopathy, or secondary pulmonary metastases from other cancers.Pathological confirmation of malignancy is the only widely accepted method of diagnosing lung cancer. Tissue is sampled from bronchoscopy where possible, and malignant cells identified by pathology. Transthoracic needle aspiration biopsy, typically using CT guidance, is used to biopsy suspicious peripheral pulmonary lesions that are not accessible with bronchoscopy. Alternatively, lymph node biopsy or biopsy during mediastinoscopy, video-assisted thoracoscopic surgery, or an open surgical procedure are used.
Cryptococcosis
Primary pulmonary infection with Cryptococcus is often clinically silent and is usually associated with exposure to soil contaminated with pigeon droppings. [29]Pulmonary manifestations of cryptococcal pneumonia are clinically indistinguishable from those of histoplasmosis pneumonia.
Sputum culture growing Cryptococcus.Serum antigen test demonstrating the presence of cryptococcal antigens.
Coccidioidomycosis
Infection is sub-clinical in the majority of patients, although symptomatic infection may be clinically very similar to histoplasmosis pneumonia.Regions endemic for Coccidioides in the US are distinct from those for Histoplasma capsulatum and include southern California, Arizona, New Mexico, and western Texas. [30]Patients with coccidioidal infection may also develop a constellation of fever, rash, and transient arthritis/arthralgia.
Enzyme immunoassay demonstrating the presence of IgM antibodies.Complement fixation assay with IgG titres of ≥1:32.
Blastomycosis
Presents as acute pneumonia in patients with a history of travel to endemic areas including south-eastern and central US states bordering the Mississippi and Ohio River basins, mid-western states, and Canadian provinces bordering the Great Lakes and areas along the St. Lawrence River. [31]Pulmonary manifestations are clinically indistinguishable from those of histoplasmosis pneumonia.
Direct examination of sputum showing yeast-like forms of Blastomyces.Sputum culture growing Blastomyces.Enzyme immunoassay and complement fixation assays demonstrating the presence of antibodies to Blastomyces.

HIV infection

EBV
EBV may resemble features of HIV acute seroconversion illness with fever, lymphadenopathy, pharyngitis, and maculopapular rash.
EBV: IgM serology and Paul Bunnell positive.HIV test negative.
Cytomegalovirus
May resemble HIV acute seroconversion illness with fever, lymphadenopathy, rash, and splenomegaly.
CMV serology positive.HIV test negative.
Influenza infection
No specific differentiating signs; viral infections such as influenza may resemble acute seroconversion illness with fever, pharyngitis, and lymphadenopathy.
HIV test negative
Common cold
No specific differentiating signs; viral infections such as the common cold may resemble acute seroconversion illness with fever, pharyngitis, and lymphadenopathy.
HIV test negative
Viral hepatitis
RUQ abdominal pain, jaundice.
Elevated LFTs.Hepatitis B or C serology positive.HIV test negative.
Secondary syphilis
Fever, malaise, pharyngitis, lymphadenopathy, maculopapular rash. Condylomata lata on genital areas and oral ulcers. May have been preceded by painless genital chancre and inguinal lymphadenopathy (primary syphilis). Can co-exist with HIV.
VDRL positive.Treponema pallidum haemagglutination test positive.HIV test negative.

HIV infection in pregnancy

Infectious mononucleosis
May see pharyngitis, splenomegaly, hepatomegaly, jaundice, rash, and myalgia.
FBC typically shows at least 50% lymphocytes, of which 10% or more are atypical. Confirmation of the diagnosis is based on a positive serum agglutination test (such as Monospot) or serological test for detection of EBV-specific antibodies directed against the viral antigens, such as viral capsid antigen and EBV nuclear antigen.
Toxoplasmosis
Difficult to differentiate clinically.
Positive serological tests for antibodies to Toxoplasma gondii. Rising antibody titres 2 to 4 weeks after initial infection, or positive IgM tests, show recent infection.
Viral hepatitis
RUQ abdominal pain, jaundice.
Aminotransferases (ALT/AST) elevated.Hepatitis serology positive.HIV test negative.
Morbilliform drug eruption
Typically presents as a maculopapular rash that develops within 2 weeks of starting treatment, but can appear up to 14 days after stopping the drug. The rash may become confluent and spares the palms and soles.
Diagnosis is usually clinical. However, FBC with differential may show leukopenia, thrombocytopenia, and eosinophilia. Serum IgE levels may be elevated. Biopsy of the skin lesion may show eosinophils, oedema, and inflammation.
Viral exanthems (enterovirus)
May see acute febrile illness and rash. Diagnosis is usually clinical, based on the specific features of the prodromal period, rash, and associated symptoms.
Tests are usually not necessary, as diagnosis is clinical. HIV tests will be negative unless the patient has concomitant HIV infection.
Parvovirus B19
Patients are typically asymptomatic.May present with 'slapped cheek' rash on the face and a lacy red rash on the limbs and trunk.Associated pain and swelling of the joints of the hands, wrists, and knees may be present.Infection in pregnancy can cause first-trimester abortion, or haemolysis in the older fetus, resulting in fetal anaemia, hypoxia, heart failure, and oedema.
Serum parvovirus B19 IgM and IgG titres are positive in recent infection.

Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL)
Short of a pathological interpretation, there are no pathognomonic clinical signs or symptoms that can differentiate Hodgkin's lymphoma (HL) from NHL. However, generalities can be helpful to differentiate the 2 entities. In contrast to NHL, HL tends to spread from one lymph node chain to another in contiguous fashion. Involvement of Waldeyer ring and extra-nodal sites is more common with NHL. Although HL and NHL can occur at any age, patients with HL tend to be younger.
Pathological confirmation, interpreted by a skilled haematopathologist, is the only method to distinguish HL from NHL. The most common NHLs that can be confused with HL are T-cell-rich large B-cell lymphoma and anaplastic CD30+ large-cell lymphoma.
Lymphadenopathy from other malignancies
A variety of different malignancies present with lymphadenopathy. Cancers of the head and neck often spread to cervical lymph nodes. Breast cancer most commonly spreads to axillary lymph nodes. Malignancies of the anus and vulva characteristically spread to inguinal lymph nodes.
In addition to the clinical context and supporting imaging studies, performing a biopsy is the best way to differentiate Hodgkin's lymphoma from other malignancies when the aetiology of an enlarged lymph node is in doubt.
Infectious mononucleosis
As opposed to HL, the enlarged lymph nodes are often tender. Sore throat is common with infectious mononucleosis but unusual with HL. Infectious mononucleosis is a risk factor for HL, with a median of 4 years between the two diagnoses. If HL is suspected, lymph node biopsy is necessary.
Blood tests can be done to test for EBV, the causative agent of infectious mononucleosis.
Reactive lymph nodes
Lymph nodes, particularly in the neck, can become enlarged from a variety of infectious/inflammatory causes. Benign lymphadenopathy typically resolves within a few weeks.
When lymph nodes persist or when other symptoms are present (B symptoms), a biopsy should be considered.

Hospital-acquired pneumonia

Atelectasis
Usually not hypoxic or febrile, although a low-grade fever may be present.
Leukocytosis and sputum production may or may not be present.Opacities on a CXR tend to be more linear than lobar shaped.
Pulmonary embolus
More acute onset of SOB, possible hypoxia, and hypocapnia.
Spiral CT scan positive; newer scans are better at detecting peripheral emboli.V/Q scans should be performed if a patient is unable to receive contrast.
ARDS
Dyspnoea and tachypnoea are common before intubation. If ARDS is secondary to an infection, a fever will be present. Furthermore, fever is a feature of fibroproliferative ARDS.
The ratio of FiO2 to PaO2 <200 supports ARDS in the context of a diffuse opacity.Patients are typically intubated and sedated and therefore a common method of diagnosis is generalised pulmonary opacity seen on CXR.
Pulmonary haemorrhage
Haemoptysis with acute haemodynamic instability. Other non-specific pulmonary symptoms include cough, dyspnoea, and chest pain.There may be a history of Goodpasture's syndrome.
CXR would show diffuse alveolar filling in a perihilar or basilar distribution. However, this is difficult to distinguish from pulmonary oedema or a diffuse infectious process. Patient may be anaemic.
Lung cancer
Similar symptoms but differentiating factor is that symptoms may have been present for many weeks.
A CT scan would be more likely to show neoplasm as a different morphology (nodular) with possible metastatic involvement of other tissue (bone).
Pleural effusion
Cough may be severe; pleurisy may be present.
A CT scan distinguishes fluid from atelectatic lung because the fluid is confined to the compartment of the pleural space, typically creating a well-defined line on imaging.
Cardiogenic pulmonary oedema
Heart failure symptoms include dyspnoea, jugular venous distention, an S3 gallop, and oedema.The concomitant presentation of HAP with an effusion or oedema makes diagnosis complicated.
CXR may show cardiomegaly, upper lobe diversion, fluid in the fissures, pleural effusion, and diffuse interstitial or alveolar shadowing.ECG may give clues as to the cause, for example, MI, ischaemia, or ventricular hypertrophy.Echocardiography can be diagnostic. B-type natriuretic peptide (BNP) may be elevated.

Human infection with avian influenza A virus

Community-acquired pneumonia
No differentiating signs/symptoms.
Isolation of organisms such as Streptococcus pneumoniae and group A Streptococcus from sputum and blood culture, and through response to typical therapy.CXR findings for typical pneumonia are consistent with consolidation.Positive H5N1-specific tests do not exclude co-infection or bacterial superinfection, although most H5N1 cases have not had bacterial co-infection identified. Seasonal influenza virus infection with bacterial co-infection is more common.
Atypical pneumonia
No differentiating signs/symptoms.
Confirmation of infection by atypical pathogens (including atypical pneumonia pathogens such as Mycoplasma pneumoniae and Legionella pneumophila) by sputum culture, blood culture, or other specific tests.Confirmed atypical pneumonia does not rule out H5N1 virus infection, but co-infection with H5N1 and atypical pneumonia pathogens has not been reported.
Endemic respiratory infections
No differentiating signs/symptoms.Respiratory infections due to pathogens endemic to the region where infection occurred should be considered (e.g., endemic mycotic infection, melioidosis in parts of Southeast Asia).
Diagnostic tests confirming infection by an atypical pneumonia do not rule out H5N1 virus infection, but co-infection with H5N1 and endemic respiratory infections has not been reported.
Seasonal influenza A or B virus infection
More common cause of morbidity in older people. Unlikely to cause serious illness in children or fit, young adults, except with invasive bacterial co-infection with 2009 H1N1 virus. More likely to be self-limited condition with milder symptoms.
Diagnostic tests confirming infection by another respiratory virus does not rule out H5N1 virus infection, but co-infection with H5N1 virus and other respiratory viruses has not been reported.
2009 H1N1 virus infection
No differentiating signs/symptoms.Both can have rapid onset of fever, cough, and pneumonia.
Diagnostic tests confirming infection by another respiratory virus does not rule out H5N1 virus infection, but co-infection with H5N1 virus and other respiratory viruses has not been reported.
Respiratory syncytial virus infection
Most common cause of lower respiratory tract infection in children aged <1 year.Significant and often unrecognised cause of lower respiratory tract infection in both older and immunosuppressed patients.Gives rise to upper and lower respiratory symptoms that peak in 3-5 days and resolve within 7-10 days.
Rapid assays using antigen capture technology are the mainstay of the diagnostic algorithm, as the identification by culture can take from 4 days to 2 weeks. [54]Diagnostic tests confirming infection by another respiratory virus does not rule out H5N1 virus infection, but co-infection with H5N1 virus and other respiratory viruses has not been reported.
Severe acute respiratory syndrome (SARS)
No differentiating signs/symptoms.Both can have rapid onset of fever, cough, and pneumonia.
The diagnosis of SARS requires high clinical suspicion and should be informed by global surveillance for infections by SARS-associated coronavirus (SARS-CoV). Tests for influenza virus are negative. Reverse transcription-PCR is positive for SARS-CoV.The absence of confirmed cases since 2004 makes the diagnosis of SARS outside of re-emergence of the virus very unlikely. [WHO: severe acute respiratory syndrome]

Huntington's disease

Tardive dyskinesia
Typically does not have a family history.Can occur in patients treated with antipsychotic medicines or metoclopramide. [32]Tends to have a distinct oral, buccal, and lingual predominance, with speech and swallowing relatively unaffected.Motor impersistence not seen.Not progressive.
The distinction between tardive dyskinesia and Huntington's disease is primarily clinical.In the unlikely event it is needed, CAG repeat testing is normal.Referral to a movement disorders consultant would typically be more cost effective.
Dentatorubro-pallidoluysian atrophy (DRPLA)
More common in Asian people but otherwise may be phenotypically indistinguishable from Huntington's disease. [33]In juvenile or early-onset cases, myoclonic epilepsy is a finding highly suggestive of DRPLA.In black patients, DRPLA may manifest without myoclonic epilepsy.
CAG repeat testing is normal, but testing for the gene for DRPLA (atrophin-1) will be positive.In black patients, MRI may demonstrate globus pallidus micro-calcifications with demyelination in the centrum semiovale (Haw River syndrome).
Neuroacanthocytosis
Often has associated areflexia and distal amyotrophy with greater prominence of oral and lingual chorea with tics and tongue biting. [34]May be phenotypically indistinguishable from Huntington's disease but inheritance is autosomal recessive.
CAG repeat testing is normal.Acanthocytes may be present on the peripheral blood smear, but repeated tests or dilution may be needed to discover them.It is helpful to direct the laboratory to comment specifically on RBC morphology.Creatine kinase is often elevated.The genetic abnormality is a frame shift mutation in the gene coding for chorein.
Benign hereditary chorea
An autosomal dominant disorder tending to be one of fairly early onset with very slow progression, without cognitive dysfunction or the other disabling features of Huntington's disease. [35] [36]Atypical features, with some functional impairment, may occur.
CAG repeat testing is normal.An abnormality can be found in the gene coding for thyroid transcription factor 1 (TTF1).
McLeod syndrome (or McLeod myopathy)
X-linked disorder; may be indistinguishable from Huntington's disease. [37]May have the additional features of axonal motor neuropathy, myopathy, cardiomyopathy, and anaemia.
FBC testing reveals acanthocytes, haemolytic anaemia.Serum creatine kinase is elevated.There is an abnormality in the gene XK (Kell erythrocyte antigen).CAG repeat testing is normal.
Spinocerebellar ataxia 17
Tends to have more prominent ataxia but may be clinically indistinguishable from Huntington's disease. [38] [39]
Genetic tests for SCA 17 reveal a CAG repeat disorder affecting the TATA binding protein.CAG repeat testing is normal.
Huntington's disease-like-1 (HDL1)
A familial prion disorder that can be phenotypically indistinguishable from Huntington's disease. [40]
CAG repeat testing for Huntington's disease is normal.Genetic testing reveals a PRNP gene mutation.Cerebellar atrophy and multi-centric plaques that stain with antiprion antibodies may be found at autopsy.
Huntington's disease-like-2 (HDL2)
Seen primarily in black patients.Phenotypically identical to Huntington's disease. [38]
CAG repeat testing for Huntington's disease is normal but a CAG/CTG repeat disorder is found in the gene for junctophilin-3.
Huntington's disease-like-3 (HDL3)
Phenotypically similar to Huntington's disease. [41] [42]
CAG repeat testing for Huntington's disease is normal.The gene for HDL3 is not known.
Neurodegeneration with brain iron accumulation (NBIA; Hallervorden Spatz syndrome)
Autosomal recessive disorder. [43]May be phenotypically indistinguishable from Huntington's disease.
MRI scan shows a characteristic hypointense globus pallidus with foci of hyperintensity ('eye of the tiger' sign).CAG repeat testing is normal.PANK2 (pantothenate kinase) mutations are present on genetic testing.
Neuroferritinopathy (NBIA2)
May be phenotypically indistinguishable from Huntington's disease. [44]Tends to have more facial action dystonia and more asymmetry of findings.
MRI shows a T2 signal loss in the basal ganglia.Serum ferritin may be decreased.CAG repeat testing is normal; mutations for the ferritin light chain (FTL) are present.
Hyperthyroid chorea
Chorea and behavioural abnormalities may be manifestations of thyrotoxicosis. [45]
Elevated thyroid function tests will be seen.CAG repeat testing is normal.
Chorea gravidarum
Typically, this is a manifestation of the first trimester of pregnancy, is non-hereditary, is of acute onset, and is not associated with other features of Huntington's disease. [46]
Pregnancy testing is positive.
Sydenham chorea
Typically seen in children or young adults. [47]Sub-acute, sometimes asymmetrical in onset, non-hereditary, and post-infectious.
Antistreptolysin O titres are elevated.
Lupus cerebritis
Rarely, chorea and/or cognitive impairment may be manifestations of CNS lupus erythematosus. [48]It is not associated with other features of Huntington's disease.
ANA titres are elevated.
Antiphospholipid antibody syndrome
May cause chorea in some patients and sometimes begins asymmetrically. [49]It is not associated with other features of Huntington's disease.
Antiphospholipid antibodies are detected.
Wilson's disease (hepatolenticular degeneration)
Associated with a progressive (usually non-choreiform) movement disorder, psychiatric and cognitive deficits, and progressive hepatic dysfunction. [50]Resembles juvenile Huntington's disease.
CAG repeat testing is normal.Serum ceruloplasmin is decreased. Serum and urine copper abnormalities, Kayser-Fleischer rings, and MRI abnormalities are readily apparent.In early cases serum ceruloplasmin may be in the low-normal range.

Hydrocele

Inguinal hernia
An incarcerated inguinal hernia may be difficult to distinguish from a hydrocele.
A groin ultrasound will show abnormal ballooning of the anteroposterior diameter of the inguinal canal. Occasionally, a segment of omentum (fat) or a segment of the bowel is seen.
Testicular cancer
These will usually be solid, firm masses that are not transilluminated. However, tumours may have reactive hydroceles surrounding them, and these will be transilluminated.
Scrotal ultrasound will confirm the diagnosis. [17] Testicular tumour markers, such as alpha-fetoprotein or beta-hCG, may also be used to indicate tumour activity.
Epididymitis
Clinically the patient has pain and tenderness in the scrotum, and local inflammatory changes can be seen. [18]
Colour Doppler ultrasonography will confirm the diagnosis. [2]
Epididymo-orchitis
Scrotal tenderness and swelling. Clinically, the patient has pain and tenderness in the scrotum, and local inflammatory changes can be seen. [18]
Color Doppler ultrasonography will confirm the diagnosis. [2]
Epididymal cyst
Scrotal mass that can be transilluminated. The position of the cyst helps the diagnosis. The cyst can be palpated separately from the testis, lying posterior and superior to it. [18]
Scrotal ultrasound may assist in making the diagnosis.
Scrotal oedema
Thickening of the scrotal wall.
Diagnosis is best made by scrotal examination. Scrotal ultrasound may be beneficial. [17]
Testicular torsion
Extreme tenderness, elevation of the testis, loss of landmarks, and absence of a cremasteric reflex are characteristic signs of torsion.
Color Doppler ultrasonography will confirm the diagnosis. [2] [9]
Varicocele
Palpation of enlarged veins during Valsalva manoeuvre is diagnostic on physical examination.
Physical examination is diagnostic, but colour Doppler ultrasonography can be used for confirmation. [2] [9]

Hypercholesterolaemia

Obstructive liver disease
Stigmata of liver disease, such as jaundice and abdominal tenderness, may be present.With significant elevations of bilirubin the patient may also complain of pruritus.
Elevated ALT, AST, gamma-glutamyl transferase, alkaline phosphatase, and bilirubin.Imaging studies such as abdominal ultrasound or CT scan and MRI may show dilated biliary ducts and possible cause for obstruction.
Nephrotic syndrome
The hyperlipidaemic response is triggered at least in part by the reduction in plasma oncotic pressure, and the severity of the hyperlipidaemia is inversely and closely related to the fall in oncotic pressure.Spontaneous or drug-induced resolution of nephrotic syndrome reverses hyperlipidaemia.
Marked elevations in plasma levels of cholesterol and, less predictably, triglycerides (TGs) and lipoprotein (a).HDL-cholesterol usually normal or reduced.Abnormal serum creatinine, urea, and serum albumin.Elevated 24-hour urinary protein.
Chronic renal insufficiency
Dyslipidaemia normally presents as hypertriglyceridaemia (due to diminished clearance).Patients undergoing peritoneal dialysis are more likely to have an atherogenic lipid profile than those undergoing haemodialysis.
About half of patients have triglyceride (TG) levels >2.7 mmol/L (>200 mg/dL), about one third have total cholesterol levels >6.2 mmol/L (>240 mg/dL), and 10% to 45% have LDL-cholesterol levels >3.4 mmol/L (>130 mg/dL).TC concentration is sometimes normal or low, which may be in part due to malnutrition in this subset of patients.Abnormal serum creatinine, urea, and serum albumin.Elevated 24-hour urinary protein.
Hypothyroidism
There may be lethargy, cold intolerance, constipation, dry hair or skin, goitre, or delayed return of deep tendon reflexes.In a study investigating people referred for the evaluation of hyperlipidaemia, hypothyroidism was found to be present in 4.2% of patients.A significant reduction in the serum cholesterol concentration during thyroid hormone replacement was only seen in those patients with a serum TSH concentration >10 milliunits/L. [26]
Serum TSH is high and serum free thyroxine may be low.

Hyperosmolar hyperglycaemic state

Diabetic ketoacidosis (DKA)
Patients are often younger, leaner, and are usually patients with type 1 diabetes.Abdominal pain is uncommon in hyperosmolar hyperglycaemic syndrome (HHS) but frequently seen (>50%) in patients in DKA. [8]In the US, patients with ketosis-prone diabetes are almost exclusively African-American or Hispanic in origin. [39]
Venous pH <7.3.HCO3 <15 mmol/L (<15 mEq/L); anion gap >12 mmol/L (>12 mEq/L).Presence of serum ketones or beta-hydroxybutyrate.
Lactic acidosis
May be clinically indistinguishable from HHS and DKA, although most patients do not have a history of diabetes.Sometimes occurs in association with HHS and DKA.
Venous pH <7.3.HCO3 <15 mmol/L (<15 mEq/L) ; anion gap >12 mmol/L (>12 mEq/L).Lactic acid >5 mmol/L.Serum glucose and ketones are normal and the serum lactate concentration is elevated.
Alcohol ketoacidosis
A history of chronic alcohol abuse is present.Produced by starvation due to poor food intake.Peripheral signs of chronic liver disease, such as spider naevi, leukonychia, palmar erythema, bruising, jaundice, scratch marks, and hepatomegaly, are present.
Venous pH is variable and can be normal.HCO3 <15 mmol/L (<15 mEq/L) ; anion gap >12 mmol/L (>12 mEq/L).Serum glucose is low or normal but serum ketones or beta-hydroxybutyrate is elevated.Lactate levels are usually elevated but elevation is insufficient to account for acidosis.
Ingestion of toxic substances
History of ingestion of ethanol, methanol, ethylene glycol (constituent of automobile antifreeze), and/or propylene glycol (diluent in many IV medications, such as lorazepam) is present.
Serum methanol levels will be elevated. [3]Calcium oxalate and hippurate crystals in the urine suggest ethylene glycol ingestion. [3]Paraldehyde ingestion is suggested by its characteristic strong odour in the breath. [3]These organic toxins can produce an osmolar gap in addition to an anion gap due to their low molecular weight. [3]
Paracetamol overdose
A history of chronic paracetamol ingestion or paracetamol overdose is present.Clinical signs include confusion, tinnitus, hyperventilation, and pulmonary oedema.
Urine and serum paracetamol levels will be positive but not necessarily in the toxic range.
Salicylate overdose
A history of chronic salicylate ingestion or salicylate overdose is present.
Serum salicylate levels will be elevated.
Seizures
Patient may have a history of prior seizure events.May present with widespread motor manifestations.
Blood chemistries may be normal.EEG will show epileptiform activity.
Cerebrovascular accident
In most cases, the symptoms of stroke appear rapidly, over seconds or minutes.Patients may present with limb and/or facial weakness (typically affects face, leg, and arm equally); may show visual disturbance.
Blood chemistries are normal.Cranial CT or MRI demonstrates haemorrhage or attenuation.

Hypersensitivity pneumonitis

Viral pneumonia
Viral pneumonias typically lasts a week or so. Acute HP lasts only a few days and recurs with each additional exposure. Ordinarily, a person should not have repeated episodes of viral pneumonia.
Bronchoalveolar lavage of both HP and viral pneumonia will demonstrate increased CD8+ cells; molecular diagnosis can identify common viral causes of pneumonia such as influenza A and B; respiratory syncytial virus; parainfluenza 1, 2, and 3; picornavirus; coronavirus; and adenovirus.
Sarcoidosis
Stage III can resemble chronic HP; HP does not have extrapulmonary manifestations.
Sarcoidosis tends to have an increased CD4/CD8 ratio following bronchoalveolar lavage.Biopsy may be necessary to differentiate.
Bronchiolitis obliterans
Can resemble chronic HP.
The diffusing lung capacity of carbon monoxide (DLCO) is normal and the PFTs are of the obstructive pattern.
Usual interstitial pneumonia (UIP)
There are no differentiating signs or symptoms.
Bronchoalveolar lavage in UIP should not show a lymphocytosis, and the histology of chronic HP tends to be bronchocentric with increased inflammation and occasional granulomata. [29] [30] [31]
Desquamative interstitial pneumonia
Patients are usually smokers or have an associated connective tissue disease.
Bronchoalveolar lavage may show an increase in brown macrophages, and sometimes neutrophils. HP tends to have lymphocytosis. [32]
Pneumoconioses
Patients should have appropriate exposure history (mineral dust or a metal).
CXR not likely to demonstrate only fibrosis; there may be pleural calcification (asbestosis) or eggshell calcification of hilar lymph nodes (silicosis).Neutrophils and causative dust particles may be found in bronchoalveolar lavage.
Silo filler's lung
May appear similar to acute HP; generally symptoms last longer as they are caused by chemical inhalation toxicity; occurs on first exposure as sensitisation is not required.
Bronchiolar lavage tends to demonstrate increased neutrophils, as opposed to lymphocytosis.
Organic toxic dust syndrome
May appear similar to acute HP; generally symptoms last longer as they are caused by chemical inhalation toxicity; occurs on first exposure as sensitisation is not required.
Bronchoalveolar lavage tends to demonstrate increased neutrophils, as opposed to lymphocytosis.
Metal fume fever
May appear similar to acute HP; generally symptoms last longer as they are caused by zinc oxide or magnesium oxide; occurs on first exposure as sensitisation is not required.
Bronchoalveolar lavage tends to demonstrate increased neutrophils, as opposed to lymphocytosis.

Hypertensive emergencies

Hypertensive urgency
Symptomatic elevated BP
History, physical examination, laboratory tests, and imaging show no evidence of end-organ damage.
Hypertension
Asymptomatic elevated BP
History, physical examination, laboratory tests, and imaging show no evidence of end-organ damage.

Hypertriglyceridaemia

Diabetes
Polyuria, polydipsia, or weight loss may occur.Retinopathy or neuropathy may be present.
Fasting blood glucose ≥7.0 mmol/L (≥126 mg/dL). Additional criteria for diabetes include HbA1c ≥6.5% or abnormal glucose tolerance test results.
Liver disease
There may be stigmata of chronic liver disease such as spider angioma or jaundice.
Aminotransferases may be elevated.Serum albumin may be low.
Hypothyroidism
Weight gain, sluggishness, dry hair/skin, delayed return of deep tendon reflexes (DTRs); goitre if Hashimoto's disease.
TSH elevated in primary hypothyroidism.In central hypothyroidism there may be laboratory evidence of other pituitary dysfunction.
Renal failure
Pruritus and breath odour.
Elevated urea/creatinine.
Medicines
History of use of oestrogens, [19] 13-cis-retinoic acid (brand: Accutane), hydrochlorothiazide, non-selective beta-blockers, [20] or antiretroviral therapy. [21]
No differentiating tests.
HIV
Possible lipodystrophy, if antiretroviral therapy.
HIV serology positive.

Hypertrophic cardiomyopathy

Athlete's heart
Patient will typically be a male endurance athlete without cardiac symptoms.No family history of HCM or sudden death.Hypertrophy will regress with cessation of exercise. [40]
Echocardiography: will characteristically show increased LV chamber dimension (LV end-diastolic dimension or LV end-diastolic >55 mm), symmetric LVH with a homogeneous-appearing myocardium.Wall thicknesses may occasionally exceed upper normal limits (12 mm). [40]LV filling pattern is most often normal. [40]The use of late gadolinium enhancement techniques may aid in differentiating HCM from an athletic heart. [21]
Discrete subaortic stenosis
No family history of HCM or sudden death.Not associated with sudden death. Systolic murmur is typically present in all positions (i.e., supine and squatting).
Echocardiography: symmetric LVH with a homogeneous-appearing myocardium and discrete fibromuscular membrane present. Normal tissue Doppler. [3]
LVH due to hypertension
Hx of long-standing hypertension.
Echocardiography: symmetric LVH with a homogeneous-appearing myocardium. [3]

Hypogammaglobulinaemia

Specific antibody deficiency
Clinical features of lesser severity.
Immunoglobulins: normal.Specific antimicrobial antibodies after immunisation: low.
Hyposplenism
May be hx of splenectomy, sickle cell disease, coeliac disease (also common in IgA deficiency).
FBC: thrombocytosis, Howell-Jolly bodies.Abdominal ultrasound: absence of or small spleen.
Complement deficiency
Complement (C)3 deficiency predisposes to pyogenic infection; C5b-9 deficiency predisposes to meningococcal and gonococcal infection.
Complement function testing: reduced.Complement component: reduced.
Mannose-binding lectin deficiency
Many patients are asymptomatic. Typically more common in infancy and in the presence of another immunosuppressive factor (e.g., after transplantation).
Mannose-binding lectin (MBL) levels: reduced.Genetic testing: MBL deficiency genotype.
Cystic fibrosis
Positive FHx of cystic fibrosis. Infants and children with untreated pancreatic insufficiency may have voracious appetites and never seem satiated. Approximately 10% to 20% of newborns may have delayed passage of meconium or even bowel obstruction with meconium. In males, examination of the scrotum may reveal bilateral absence of the vas deferens.
Sweat test: positive (sweat chloride ≥60 mmol/L [≥60 mEq]).Immunoreactive trypsinogen test: positive.Genetic testing: presence of 2 disease-causing mutations.
Anatomical anomalies of sinuses/lungs
Other known congenital defects.
CT chest and sinuses: abnormalities visible such as obstructive bronchial lesions (e.g., neoplasms in older patients).

Hypogonadism in men

Pituitary macro-adenoma
Headache and bi-temporal hemianopia symptoms related to other pituitary hormonal deficiencies; for example, weight loss and nausea due to adrenal insufficiency, or cold intolerance and constipation due to hypothyroidism.
Low LH and FSH levels with pituitary macro-adenoma.Possible low TSH, growth hormone and cortisol levels.MRI of the pituitary reveals pituitary lesion.
Prolactinoma
Headache, bi-temporal hemianopia, and occasional galactorrhoea.
MRI of the pituitary reveals pituitary lesion.Serum prolactin elevated.
Hyperprolactinaemia
Galactorrhoea may be present.Headache may be present if hyperprolactinaemia is secondary to prolactinoma.
Elevated prolactin levels. Hypothyroidism and medicines such as dopamine antagonists should be excluded.
Depression
Depression resulting in reduced libido.Psychogenic erectile dysfunction.
With depression, hormonal tests may be normal.Normal early morning erections will still occur if erectile dysfunction is psychogenic.

Hypoparathyroidism

Hypovitaminosis D
Poor diet, short gut, lack of sunlight, malabsorption or other mechanism leading to fat-soluble vitamin deficiency.
The best differentiating test is a low or inappropriately normal PTH with hypoparathyroidism, and elevated PTH with hypovitaminosis D.Plasma 25-hydroxyvitamin D3 normal range 10 to 68 nanogram/mL (24.9-169.5 nanomol/L).Serum 1,25-dihydroxyvitamin D3 (active form), normal range 25 to 45 picogram/mL (60-108 picomol/L).
Hypomagnesaemia
Hypocalcaemia symptoms out of proportion to calcium deficiency.Hypomagnesaemia may be the sole cause of hypocalcaemia or may aggravate relative hypoparathyroidism.
Serum magnesium low. Serum calcium may be normal or low.
Hypoproteinaemia
May be asymptomatic. If severe, may have third spacing of fluid (oedema, anasarca, ascites).
Low serum protein (normal value 55-80 g/L [5.5-8.0 g/dL]) and albumin (normal 35-55 g/L [3.5-5.5 g/dL]).About half of the total calcium is bound to serum protein, largely to albumin. If albumin is low, total calcium will be low, although there may be no physiologic deficiency. For US units (calcium in mg/dL; albumin in g/dL), the formula for corrected serum calcium is (0.8 x (normal albumin - patient’s albumin)) + serum calcium. For SI units (calcium in mmol/L; albumin in g/L), the formula for corrected serum calcium is (0.02 x (normal albumin - patient’s albumin)) + serum calcium. However, formulae used to calculate corrected calcium only provide an approximation, and this measurement may not be reliable for the critically ill patients. [9] [10] Measurement of ionised calcium is preferred.Physiological calcium may be directly measured by checking ionised calcium.
Respiratory alkalosis
Hyperventilation may be organic (anxiety, compensatory) or may be iatrogenic (mechanical ventilation).
Normal serum calcium despite symptoms. ABG shows high pH and low PaCO2 consistent with hyperventilation. Intravenous calcium will temporarily alleviate symptoms but the response in hyperventilation will be brief.
Renal failure
Symptoms may be related to diminished clearance rate for renally cleared medication; at end stage, oliguria or anuria, pruritus, mental status changes, volume overload.
PTH is usually elevated in hypocalcaemia due to renal disease.Elevated serum urea, creatinine.Serum phosphorus is usually high in renal failure rather than low as in hypoparathyroidism.

Hypopituitarism

Addison disease
Hyperpigmentation due to high levels of ACTH that stimulate melanocyte production of melanin.Postural hypotension as the zona glomerulosa is destroyed; in contrast, the zona glomerulosa is preserved in secondary adrenal insufficiency as it is still maintained under the regulation of the renin-angiotensin-aldosterone system.
ACTH level is markedly elevated.Electrolyte abnormalities (hyponatraemia and hypokalaemia) are more common.
Primary hypothyroidism
There are no classic symptom differences between patients with primary or secondary hypothyroidism. On physical examination, patients with primary hypothyroidism are more likely to have a goitre.
Elevated TSH.
Shock (cardiogenic or septic)
Patients with cardiogenic shock may relate a history of prior cardiac problems.Patients with septic shock will be febrile with an elevated white cell count.
Cardiogenic shock is responsive to fluid resuscitation and septic shock is responsive to fluid resuscitation and antibiotics; in contrast, patients with hypopituitarism are unresponsive to fluid resuscitation and the haemodynamic status only responds after corticosteroids are initiated.

Hypothermia

Sepsis
Patients may present with rigors, but septic patients tend to have a fever as opposed to a lowered temperature.
Blood and urine cultures and tracheal aspirate with Gram stain analysis show a pathogen. FBC may show elevated WBC as well.
Hypothyroidism
Cases that mimic hypothermia most commonly result from long-standing hypothyroidism. Typical symptoms include cold intolerance, fatigue, weight gain, constipation, a deep voice, coarse hair, and dry skin.Severe hypothyroidism may result in myxoedema coma. Myxoedema refers to non-pitting oedema of skin and soft tissue. An associated change in level of consciousness (not necessarily coma) is present.Concurrent infection or noncompliance with thyroid replacement medications may precipitate myxoedema coma in a patient with hypothyroidism.
Thyroid function tests show a high TSH and low free T4/T3.

Hypoventilation syndromes

Interstitial lung disease
Patients with interstitial lung disease often complain of shortness of breath, especially exertional dyspnoea. In addition, they may complain of a non-productive cough. Patients can present with a rapid, shallow breathing pattern, inspiratory crackles on examination of the lungs, and clubbing of the digits.
While pulse oximetry may reveal an SaO2 <90%, arterial blood gas analysis demonstrates hypocapnia rather than hypercapnia associated with hypoxaemia.CXR demonstrates interstitial changes and fibrosis, which can be confirmed with a CT scan.
Obstructive sleep apnoea (OSA) without associated alveolar hypoventilation
Patients with OSA without associated alveolar hypoventilation present with symptoms of excessive daytime sleepiness and loud snoring. On examination, obesity without signs of cor pulmonale such as lower-extremity oedema is common, although one third of patients have a BMI <30 kg/m^2.
Arterial blood gas analysis demonstrates a normal PaCO2, and pulse oximetry while awake reveals a SaO2 >90%.Overnight polysomnogram shows obstructive apnoeas and hypopnoeas with nocturnal oxygen desaturation purely associated with the sleep-disordered breathing events.

Ichthyosis

Asteatotic dermatitis (eczema craquele)
Ichthyosis is not a specific diagnosis and is used more as a descriptive term describing scaling that is present in a number of different conditions. Scaling is also a finding in patients with severely dry skin, which, in certain instances, can become inflamed. When the skin takes on a 'dry river bed' appearance, with superimposed inflammation, this is referred to as eczema craquele, or asteatotic eczema.
Clinical diagnosis.
Atopic dermatitis
Inflamed, itchy skin that commonly occurs in patients who also demonstrate other features of epithelial hypersensitivity, such as asthma or environmental allergies.Ichthyosis vulgaris often occurs in the setting of atopic dermatitis, so these 2 clinical conditions may exist together in the same patient.
Clinical diagnosis.
Psoriasis
Also may present with hyperkeratosis. However, tends to be well circumscribed, with a fine, silvery scale, compared with the relatively larger scales that are seen in ichthyosis.
Usually a clinical diagnosis.If there is uncertainty, a skin biopsy may show classical features including intra-epidermal spongiform pustules and Munro's neutrophilic micro-abscess within the stratum corneum, parakeratosis, and epidermal acanthosis with dilated capillaries within dermal papillae.

Idiopathic inflammatory myopathies

Hereditary inclusion body myositis
Quadriceps more likely to be spared but not always.May be associated with leukoencephalopathy.
Absence of inflammation on muscle biopsy more likely in hereditary inclusion body myositis. [1]
Oculopharyngeal muscular dystrophy
Clinical features include ptosis and dysphagia, occasionally with proximal limb weakness.
Muscle biopsy shows rimmed vacuoles and tubular filaments with an absence of inflammatory features. [54]
Late-onset distal myopathy
Progressive muscular weakness and atrophy beginning in hands or feet.
Muscle biopsy may show rimmed vacuoles and tubulofilamentous inclusions in several types of distal myopathy (e.g., Welander's, Udd's, Markesbery-Griggs, Laing's, distal myopathy), but there is an absence of inflammation. [5]
Overlap myositis
Symptoms of polymyositis or dermatomyositis associated with some other connective tissue disorders.Diagnostic criteria for the two different disorders are fulfilled.
Additional serological features diagnostic of an underlying connective tissue disease (e.g., SLE, rheumatoid arthritis, scleroderma, or mixed connective tissue disease). [5]
Amyotrophic lateral sclerosis (motor neuron disease)
Upper motor neuron signs (not present in idiopathic inflammatory myopathies).
EMG shows fasciculation potentials (rare in idiopathic inflammatory myopathies), and neurogenic changes are more apparent.Muscle biopsy shows neurogenic changes.
Myasthenia gravis
Weakness more likely to fluctuate, increasing with repeated or sustained exertion.Involvement of extra-ocular muscles is common.Spontaneous remissions can occur.
EMG typically shows abnormal decrement in repetitive nerve stimulation and increased jitter in single-fibre EMG.Presence of antibodies to acetylcholine receptors or muscle-specific kinase.
Drug-induced myopathy
History of medication associated with development of myopathy (e.g., lipid-lowering drugs, D-penicillamine, laxative abuse).Withdrawal of implicated drug may reverse the myopathic damage.
No differentiating tests.
Acid maltase deficiency
More likely to develop respiratory failure (occurs in approximately one third of patients, may be the presenting symptom).
At rest, EMG may show myotonic discharges.Muscle biopsy tissue or cultured skin fibroblasts show a reduction of acid alfa-glucosidase activity.
Secondary metabolic myopathy
Muscle weakness co-exists with systemic manifestations of specific metabolic or endocrine abnormalities, such as hypokalaemia, hypophosphataemia, hypothyroidism, hyperthyroidism, and hyperparathyroidism.Restoration of muscle strength may occur after correction of the metabolic or endocrine condition.
Abnormal blood tests indicating the presence of endocrine or metabolic diagnosis (e.g., low serum potassium or abnormal thyroid function tests).
Chronic inflammatory demyelinating polyneuropathy
Weakness is usually both proximal and distal, and mildly asymmetrical.Sensory symptoms and signs and diffuse hypo-/areflexia are prominent.
Nerve conduction studies show signs of primary demyelination.Needle EMG shows neurogenic pattern and no signs of myopathy.Serum CK is typically normal.
Scleroderma
Muscle weakness more likely to be low-grade if present.
Mostly mild or absent elevation of serum CK.EMG shows no or little spontaneous activity.Muscle biopsy may reveal perimysial fibrosis, scleroderma vasculopathy, and type 2 fibre atrophy with little muscle fibre destruction. [5]

Idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) associated with left heart diseases (pulmonary venous hypertension)
Older patients, male preponderance, usual cardiovascular risk factors (diabetes, hypertension, smoking). Left ventricular gallops and mitral valve murmurs.
Transthoracic echo: left atrial enlargement, left ventricular systolic and/or diastolic dysfunction, mitral valve disease. [35]Right heart catheterisation: elevated pulmonary capillary wedge pressure, transpulmonary gradient <12 mmHg.Left heart catheterisation: coronary disease, elevated left ventricular end-diastolic pressure.
PAH associated with lung respiratory diseases and/or hypoxia
COPD: >40 to 50 years old, history of smoking, chronic cough and sputum production, decreased breath sounds, wheezing.Interstitial lung disease: history of occupational exposures, drug use, smoking, or connective tissue disease; chronic non-productive cough, bibasilar inspiratory crackles, digital clubbing.Sleep-disordered breathing (e.g., obstructive sleep apnoea): loud snoring, excessive daytime sleepiness, morning headaches, obesity, mild elevations in pulmonary artery pressure.Alveolar hypoventilation disorders: obesity-hypoventilation syndrome, neuromuscular disease.
PFTs: obstructive or restrictive defect.ABG: hypoxaemia, hypercapnia.Overnight oximetry: de-saturation, screening for sleep apnoea.Polysomnography: obstructive sleep apnoea.High-resolution chest CT scan: emphysema, interstitial lung disease.
PAH due to chronic thrombotic and/or embolic disease
History of pulmonary embolism; bruits over the lung fields (pulmonary flow murmurs) are present in 30% of cases and they are not present in IPAH. [37]
Ventilation-perfusion lung scintigraphy: one or more segmental-sized or larger unmatched perfusion defects. [35]Pulmonary angiography: vascular webs or band-like narrowings, intimal irregularities, pouch defects, abrupt and angular narrowing, proximal obstruction. [37]
PAH associated with: connective tissue disease
Multi-system organ involvement: skin lesions, arthralgias/arthritis, GORD, Raynaud's phenomenon, oral ulcers, serositis, renal disease, haematological abnormalities, etc.Scleroderma: especially the limited form (CREST syndrome: calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactily, and telangiectasis) in the absence of interstitial lung disease. Less severe in the diffuse form of scleroderma. [35]Less common in SLE, mixed connective tissue disease, and rheumatoid arthritis.
Antinuclear antibodies >1:80 titre. [35]Anti-centromere antibodies in limited scleroderma. [33]Anti-U3-ribonucleoprotein (RNP) antibodies in diffuse scleroderma.Anticardiolipin antibodies in lupus.Rheumatoid factor.
PAH associated with: congenital systemic to pulmonary shunts
Simple shunts (more common than complex): ventricular septal defect (highest risk, especially if >1 cm), atrial septal defect (especially if >2 cm and sinus venosus type), patent ductus arteriosus, anomalous pulmonary venous return. [4]Complex shunts: truncus arteriosus (almost all patients develop PAH), atrioventricular septal defects. [4]For all defects, risk of PAH is highest if unrepaired. [4]Eisenmenger's physiology: secondary erythrocytosis, iron deficiency, haemoptysis, 'paradoxical' embolisation, brain abscesses. [38]
Contrast echocardiography with agitated saline ('bubble'): best for shunt reversal (right-to-left). [35]Transoesophageal Doppler echocardiography and/or cardiac MRI: [38] anatomical definition.Right and left heart catheterisation with oxygen saturation measurement. [35]
PAH associated with: portal hypertension (portopulmonary hypertension)
Mean age of presentation is the fifth decade of life; male-to-female ratio of 1.1:1. [39]Signs of underlying liver disease: jaundice, spider telangiectasia lower extremity oedema, ascites.
LFTs: abnormal. [4]Abdominal ultrasound with colour Doppler: liver cirrhosis, increase in the transhepatic venous gradient.Right heart catheterisation: increased gradient between free and occluded (wedged) hepatic vein pressure.
PAH associated with: HIV infection
HIV risk factors.
Positive HIV serology.
PAH associated with: drugs and toxins
Hx of appetite-suppressant use: aminorex, fenfluramine derivatives, [28] use of methamphetamine. [30]
Abnormal toxicology.
PAH associated with: other medical disorders
Hx of thyroid disease, haemoglobinopathies, myeloproliferative disorders, splenectomy. [4] [35]
Abnormal TFTs, FBC with platelet count. [4] [35]
Pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis
Digital clubbing and/or basilar rales on examination. [4]
More severe hypoxaemia and decreased in diffusing capacity of the lung for carbon monoxide. [4]CT chest: ground-glass opacities with a centrilobular distribution, septal lines, and adenopathy.Elevated numbers of haemosiderin-laden macrophages in bronchoalveolar lavage fluid.

Idiopathic pulmonary fibrosis

Non-specific interstitial pneumonia
More commonly associated with collagen vascular disease; therefore, patients may have skin, joint, or other systemic manifestations.
More ground-glass opacities on chest CT, absence of honeycombing.Presence of auto-antibodies if secondary to an underlying connective tissue disease. [45]
Cryptogenic organising pneumonia
Formerly called bronchiolitis obliterans-organising pneumonia or BOOP; more commonly associated with prior infection or collagen vascular disease.Systemic manifestation of weight loss, fever, joint symptoms, and rash are more common. [46]
Patchy consolidation, isolated nodules, or infiltrative reticulation on chest CT. [46]
Acute interstitial pneumonia (AIP)
Occurs over weeks in a previously healthy individual, often with 'influenza-like' prodrome.AIP is rare and frequently progresses to hypoxaemia and respiratory failure. [44]
Chest imaging demonstrates diffuse bilateral ground glass or frank alveolar filling pattern. [45]
Respiratory bronchiolitis-associated interstitial lung disease
Similar respiratory symptoms.Affects people who smoke. [44]
Diffuse fine nodular or reticular changes on chest CT. [45]Combined obstruction and restriction on PFTs. [1]
Desquamative interstitial pneumonia
Rare, affects people who smoke, sub-acute illness, no scarring fibrosis. [1]
Diffuse ground-glass opacities on CT.Restrictive pattern on PFTs. [45]
Lymphoid interstitial pneumonia
Often secondary to Sjogren's syndrome, HIV, or a dysproteinaemia, so patients may have signs/symptoms of those diseases.
Nodules, ground-glass opacities, reticulation, and thin-walled cysts may be present on CT. [45]
Connective tissue disease-associated IPF
Skin, joint, or other serological abnormalities will be present. [47]Rash may be present.
May have less 'typical' chest CT with less peripheral predominance.Presence of autoantibodies related to connective tissue.
Drug-related pulmonary fibrosis
Respiratory symptoms similar to those of IPF will be related to exposure to medications such as amiodarone, nitrofurantoin, and bleomycin, which are thought to cause pulmonary fibrosis.
Chest CT and PFTs are non-specific.
Asbestosis
History of asbestos exposure.Physical findings will be normal in pleural disease unless the pleural thickening is diffuse or there is a benign pleural effusion. In these cases, breath sounds will be diminished on auscultation and dullness to percussion may be present.
Pleural plaques may be present on chest imaging; ferruginous bodies can be found on biopsy. [47]
Hypersensitivity pneumonitis
Respiratory symptoms are typically associated with acute exposure to causal antigen such as bacteria or mould in silage or hay.
Presence of IgG antibodies in the blood to the causal antigen, a ground-glass appearance on high-resolution CT, and granulomas on lung biopsy.
Sarcoidosis
Extra-pulmonary involvement.By comparison with IPF, younger patients affected.
Lymphadenopathy is more evident on chest imaging. [47]
Langerhans' cell histiocytosis
Rare disease.History of smoking and spontaneous pneumothorax.
Cystic disease with nodules in upper- and mid-lung zones on chest CT.
Lymphangioleiomyomatosis
Rare disease.Pre-menopausal women are affected; spontaneous pneumothorax is common.
Thin-walled cystic disease throughout the lung; combined obstruction and restriction on PFTs.

Idiopathic thrombocytopenic purpura

Pseudothrombocytopenia
A spuriously low count in disodium ethylenediaminetetraacetate (EDTA) occurs in 0.1% of adults. It is important to recognise this condition when it occurs because it is benign, and so potentially dangerous diagnostic tests and treatments can be avoided.
Ex-vivo agglutination, or clumping, can lead to spuriously low platelet counts on automated counters because the machine is unable to detect and count the individual platelets that make up a clump. This may account for up to 15% to 30% of all cases of isolated thrombocytopenia. [13]Peripheral smear shows platelet clumps.Platelet satellitism, where platelets form a ring around neutrophils, may also be seen.
Congenital impaired platelet production
This is a broad category, which includes several congenital syndromes. The bleeding may be worse than expected for the platelet count reported, as platelet function may also be impaired in addition to impaired platelet production.Congenital disorders may have associated facial dysmorphism, heart defects, mental retardation, skeletal abnormalities, high-tone sensorineural deafness, nephritis and cataracts.
Macrothrombocytes and Dohle body-like inclusions in leukocytes on peripheral smear.A subpopulation of platelets with giant alpha granules is seen in Paris-Trousseau syndrome.Platelet function analyser (PFA-100) testing may indicate prolonged time to clotting, which suggests impaired function.
Thrombocytopenia related to liver disease or alcohol ingestion
Large amounts of alcohol consumption can directly suppress bone marrow production of platelets. [14] Thrombopoietin is produced in the liver and so severely impaired liver synthetic function can lead to a decrease in platelet production stimulation.Physical examination may demonstrate signs of liver failure including splenomegaly, ascites, varices, spider angiomata, palmar erythema and gynaecomastia.Massive splenomegaly from liver disease can lead to exaggerated splenic pooling and thrombocytopenia.
Elevated gamma-GT, alkaline phosphatase, ALT and AST.Prolonged prothrombin time.Decreased serum albumin.Megaloblastic peripheral smear with macrocytic RBC, hypersegmented neutrophils and Howell-Jolly bodies (chromosomal remnants in RBC) suggests vitamin B12 or folate deficiency.
Thrombotic thrombocytopenic purpura (TTP)
May demonstrate neurological changes or fever as well as signs of anaemia and thrombocytopenia.
FBC shows anaemia and thrombocytopenia with fragmented red blood cells (schistocytes) on blood smear (microangiopathic film).Elevated creatinine.Protein and blood present on urinalysis.
Malignant hypertension
Patients have severely elevated blood pressure.
FBC shows a microangiopathic picture with anaemia, thrombocytopenia and fragmented red blood cells (schistocytes) on blood smear.
Disseminated intravascular coagulation (DIC)
DIC is a disorder of coagulation that occurs in the setting of other medical conditions such as sepsis, trauma, malignancy, pregnancy, and amniotic fluid embolism.Patients are usually very unwell with significant bleeding due to coagulation defects.
FBC shows a micro-angiopathic picture with anaemia, thrombocytopenia and fragmented red blood cells (schistocytes) on blood smear.Prolonged prothrombin time and activated partial thromboplastin time.Elevated D-dimer.
Sepsis
Patients with sepsis can develop thrombocytopenia. These patients have hypotension, fever and other signs of sepsis. Treatment of the underlying infection should correct the thrombocytopenia.
Elevated white cell count with left shift.Peripheral smear may show vacuoles in the cytoplasm of neutrophils, which is highly specific for bacteraemia.Blood cultures may be positive.Thrombocytopenia and anaemia are often related to a concurrent DIC phenomenon.
Severe pre-eclampsia
New blood pressure elevation and proteinuria after 20 weeks' gestation in pregnant women.
Elevated urinary protein.
Haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome
Typically, occurs in pregnant women who are already being followed up for gestational hypertension or pre-eclampsia.Patients are hypertensive and may complain of headache, nausea and abdominal discomfort.
Low haemoglobin, low haptoglobin and elevated unconjugated bilirubin consistent with haemolytic anaemia.Elevated LFTs.Low platelets.May have abnormal coagulation studies if DIC present.
Gestational thrombocytopenia
In general, gestational thrombocytopenia is more common and milder with platelet counts >70 x 10^9/L (>70 x 10^3/microlitre). It occurs in late gestation and recovers completely after delivery.Gestational thrombocytopenia has no risk to the baby, whereas ITP in pregnancy can cause thrombocytopenia in the newborn.
There is no absolute test to differentiate between gestational thrombocytopenia and ITP in pregnancy.
Myelodysplastic syndromes (MDS)
MDS is a rare cause of isolated thrombocytopenia. Incidence increases with age so bone marrow biopsy (which can differentiate ITP from MDS) is recommended in the work-up of patients over 60 years of age with isolated thrombocytopenia.Hepatomegaly, splenomegaly and lymphadenopathy are uncommon but may be present.
FBC usually shows a decrease in other cell lines but isolated thrombocytopenia can occur in up to 5% of cases. [15]PFA-100 test shows abnormal platelet function.Bone marrow biopsy is diagnostic.
Type IIB von Willebrand's disease
Autosomal-dominant disorder so may have known family history.A gain-of-function mutation in von Willebrand factor results in binding to platelets and clearance of platelets from the circulation.These patients have bleeding out of proportion to their platelet count.
Decreased von Willebrand factor activity.Increased ristocetin-induced platelet aggregation.Decreased large von Willebrand factor multimers on electrophoresis.
Splenomegaly/hypersplenism
Splenomegaly can lead to a reversible pooling of up to 90% of the total body platelet count whereas hypersplenism results in early destruction of platelets in the spleen.Patients may have palpable splenomegaly and signs of the underlying cause of splenomegaly, such as lymphadenopathy in lymphoma or jaundice and spider nevi in portal hypertension due to liver disease. Consider also a diagnosis of Gaucher's disease and other thesaurismoses.
Ultrasound and CT scan will show splenomegaly.
Drug-induced thrombocytopenia
A thorough medicine and herbal supplement history is important for identifying potential offending drugs.Many drugs have been implicated including quinidine, quinine, rifampin and bactrim. Herbal remedies can also be implicated including tonic water (contains quinine) and tahini (a component of hummus).Resolution of thrombocytopenia when drug ceased.
Diagnosis is clinical.
Heparin-induced thrombocytopenia (HIT)
A medicine history will reveal the use of heparin or low-molecular-weight heparin.HIT affects up to 5% of patients exposed to heparin. Thrombocytopenia usually occurs 5 to 14 days after starting heparin therapy (but can occur sooner if there has been a prior heparin exposure).Up to 50% of patients with HIT can develop thrombosis if not treated properly with alternative anticoagulation (i.e., the use of a direct thrombin inhibitor) so cessation of heparin alone is inadequate. [16]
A heparin aggregation study demonstrates the presence of platelet aggregation when exposed to heparin. This is caused by antibodies to platelet factor 4.

IgA nephropathy

Henoch-Schonlein purpura (HSP)
Characterised by the presence of systemic symptoms, including purpuric rash (90% of cases); abdominal pain (85% of cases); joint pain (70% of cases); peripheral oedema; and GI bleeding.HSP is not recurrent or persistent. [2]
There are no differentiating tests, and histopathological findings are very similar. [2]
Thin glomerular basement membrane disease
More common in females.Does not usually progress to end-stage renal disease.Gross haematuria is uncommon. [3]
Under electron microscopy the basement membranes appear diffusely attenuated and there is no mesangial expansion under light microscopy.Immunofluorescence studies do not demonstrate IgA deposits within glomeruli. [3]
Hereditary nephritis (Alport's disease)
Family history of renal failure, primarily in males.This is an X-linked dominant disorder associated with neural hearing loss and ocular abnormalities. [3]
Electron microscopy shows longitudinal splitting and thickening of the lamina densa of the glomerular basement membrane.In addition, a3, a4, and a5 chains of type IV collagen are absent in the basement membrane.
Post-streptococcal glomerulonephritis
Develops within 1 to 3 weeks after the onset of streptococcal infection.hypertension and oedema frequently occur.Recurrent haematuria is not characteristic.
Elevated levels of antibodies to streptococcal antigens (anti-streptolysin O or anti-DNase B) are a good diagnostic clue.C3 is usually low in the first 2 weeks of infection.

Ileus

Mechanical bowel obstruction
Localised pain; symptoms start acutely.
Shares many of the same signs and symptoms as ileus, so differentiating can be challenging. Obstructive series shows step-wise air-fluid levels and very dilated loops of small bowel.CT scan shows a transition zone (dilated loops leading up to collapsed loops of bowel), and oral contrast does not reach distal to the point of obstruction.
Pseudo-obstruction (Ogilvie's syndrome)
Crampy abdominal pain, anorexia. Typically seen in bed-bound, older, or chronically ill patients with polypharmacy. [41] [42]
X-rays show isolated large bowel dilatation.CT scan or gastrograffin enema will show no evidence of mechanical obstruction.
Gastroenteritis
Hx should indicate a likely gastroenteritis, along with symptoms of diarrhoea. It is generally self-limited.A patient with no risk factors for ileus who is also having diarrhoea is likely to have gastroenteritis.
Clinical diagnosis. Further testing may be non-specific and unhelpful.
Pancreatitis
Acute abdominal pain.
Elevated amylase and lipase.May have gall stones on RUQ ultrasound.Abdominal CT scan shows diffuse or segmental enlargement of the pancreas with irregular contour and obliteration of the peri-pancreatic fat, necrosis, or pseudocysts.
Acute cholecystitis
Pain in the epigastrum and right upper quadrant of the abdomen.
Distended gallbladder, thickened gallbladder wall, and presence of gall stones on RUQ ultrasound.Abdominal CT scan shows gallbladder wall inflammation; linear high density areas in peri-cholecystic fat tissue.
Bowel perforation
Severe abdominal pain, fever.
Abdominal x-ray demonstrates free intraperitoneal air.A CT scan demonstrates bowel perforation.
Intra-abdominal abscess
Fever, anorexia, crampy abdominal pain and tenderness.
A CT scan demonstrates abscess.
Peritonitis
Pain and tenderness of the abdominal wall. Hx and physical examination to evaluate for risk factors and elicit signs of peritonitis.
A CT scan demonstrates peritonitis.
Intestinal pneumatosis
Diarrhoea, bloody stools, abdominal pain.
A CT scan demonstrates pneumatosis.

Iliotibial band syndrome

Biceps femoris tendinopathy
Pain over the biceps femoris.Pain with resisted knee flexion.
Clinical differentiation usually suffices.
Degenerative joint disease
Joint line pain or diffusion.
X-ray shows new bone formation (osteophytes), joint space narrowing, and subchondral sclerosis and cysts.
Lateral collateral ligament (LCL) sprain
Pain over the LCL.Pain provocation with various stress tests.Varus instability test to check the LCL. With the patient lying flat and the knee held at about 30° of flexion, the shin is shifted to the medial side. Insufficiency of the LCL will allow the knee to 'open up' excessively. The test is repeated with the leg straight. If the knee still opens up excessively, then more than just the LCL is torn.
Clinical differentiation usually suffices.
Lateral meniscal tear
Joint line tenderness.Positive McMurray's test. The McMurray's test is performed with the patient lying flat (non-weight bearing) and the examiner bending the knee. A click is felt over the menuscus tear as the knee is brought from full flexion to 90° of flexion.
MRI shows signal changes within meniscus on T1 and T2 images; sagittal views: anterior and posterior meniscal tears; coronal view: far medial and far lateral meniscal tears.
Myofascial pain
Pain in the muscle belly.Referred pain with palpation of trigger point.
Clinical differentiation usually suffices.
Patellofemoral stress syndrome
Anterior knee pain.Tenderness in the lateral patellar set.Positive patellar compression test. The test is performed by compressing the patella down into the trochlear groove as the patient flexes and extends the knee.
Clinical differentiation usually suffices.
Popliteal tendinopathy
Tenderness of the popliteal tendon.Positive figure of 4 test.Positive Garrik's test. The test is performed with the patient supine; the knee is flexed to 90°, the leg internally rotated, and the patient is asked to resist the examiner's attempt to externally rotate the tibia.
Clinical differentiation usually suffices.
Referred pain from lumbar spine
Pain provocation with straight legs raised or swamp test.
X-ray: plain radiographs should be obtained if pain is not settling after 6 to 8 weeks.MRI or CT: considered if neurological compromise, infection, or tumour is suggested by clinical evaluation.
Stress fracture
Pain with palpation over bone.
MRI: demonstrates fracture.Bone scan: evidence of uptake correlating with the area of pain.
Superior tibiofibular joint sprain
Tenderness of the tibiofibular joint.Instability testing of the tibiofibular joint.
Clinical differentiation usually suffices.

Impetigo

Herpes simplex
Monomorphic grouped vesicles.
Viral PCR.Viral direct immunofluorescence swab or viral culture and Tzanck prep when PCR unavailable.
Varicella
Widespread vesicles at different stages.Oral mucosa may be affected.
Viral PCR.Viral direct immunofluorescence swab or viral culture and Tzanck prep when PCR unavailable.
Dermatophytosis (Tinea corporis, Tinea capitis)
Peripheral scale.Central clearing.Crusting infrequent except in scalp kerion.Bullous dermatophytosis commonly occurs on the instep of the foot.
Microscopy of skin scrapings and fungal culture.
Candida
Satellite lesions.Affected areas are usually more confluent.
Bacteriology swab for culture.
Discoid dermatitis
Pruritus invariably present.Very fine circular scaling or vesicles.
Skin biopsy confirmatory.
Pemphigus vulgaris
Larger superficial blisters may be seen early. Seen more commonly in older patients.Prominent mucosal involvement.
Skin biopsy confirmatory.Immunofluorescence helpful.
Stevens-Johnson syndrome
Involvement of the conjunctiva.Patient systemically ill.
Skin biopsy confirmatory.
Bullous erythema multiforme
Target lesions with violaceous centre.Patient uncomfortable.
Skin biopsy confirmatory.
Dermatitis herpetiformis
Multiple vesicles grouped on the lower back and around the elbows and knees.Intensely pruritic vesicles.
Skin biopsy confirmatory.

Infantile colic

Urinary tract infection
In the first few months of life the symptoms of UTI are often non-specific and include fever, irritability, lethargy, poor feeding, and poor weight gain.Malodorous urine is highly suggestive.
Positive urinalysis and culture.
Otitis media
Usually aged >6 months. Self-limiting (rarely lasts >3 weeks).Presents with fever, irritability, and persistent crying. Some infants poke or tug at the affected ear.Tympanic membrane is hyperaemic, bulging, and opaque with poor or no mobility.Otorrhoea indicates perforation of the ear drum.
Clinical diagnosis.
GORD
Regurgitation is present at birth and becomes more pronounced in the second or third week of life. The regurgitation is often effortless and is worse after meals when the infant is in a recumbent position, or when pressure is applied to the abdomen.Some infants may present with complications such as failure to thrive, aspiration pneumonia, and gastrointestinal bleeding.
The diagnosis is mainly clinical. When the diagnosis is ambiguous or when complications are suspected, further investigations may be warranted.Barium swallow and fluoroscopy may show the gastro-oesophageal reflux and the presence of peptic oesophagitis.Radionuclide gastro-oesophagography is a non-invasive test to demonstrate gastro-oesophageal reflux. Gastro-oesophageal reflux associated with the appearance of radiotracer in the lung provides evidence that respiratory symptoms are related to the reflux.24-hour intra-oesophageal pH monitoring can be used to diagnose gastro-oesophageal reflux and determine its severity.
Intussusception
Colicky abdominal pain, irritability, lethargy, vomiting, and passage of 'currant-jelly' stool.The pathognomonic sign is an elongated mass in the RUQ or epigastrium with a feeling of emptiness in the right lower quadrant (Dance's sign).
Plain abdominal x-rays may show dilated loop of intestine, air-fluid levels, paucity of air in the right lower quadrant, minimal faecal content, and a soft mass in the right or mid abdomen.Abdominal ultrasonography may show a tubular mass (sandwich or pseudokidney sign) in longitudinal views and a target appearance (doughnut sign) in transverse views.If doubt remains, the diagnosis can be confirmed by x-ray with barium or air insufflation; both procedures are therapeutic as well as diagnostic.
Fracture
History of trauma.Pain and tenderness at the affected site and inability to move the affected part are characteristic.Bruises and swelling in the adjacent area.
X-ray of the affected area confirms the fracture.
Anal fissure
Blood is generally present on the surface of the stool. Constipation is common.Physical examination shows a fissure in the anal area. The fissure is often posterior, below the dentate line.
Clinical diagnosis.
Pyloric stenosis
Typically develops in a 3- to 6-week-old infant, but may be seen between 2 and 12 weeks.Presents with projectile non-bilious vomiting after feeding.An upper abdominal mass (olive) may be detected by palpation.
Abdominal ultrasound shows a pyloric channel length >17 mm and pyloric muscle thickness >4 mm.

Infantile spasms

Severe myoclonic epilepsy of infancy (Dravet's syndrome)
An intractable epilepsy with seizure onset in the first year of life.Affected children have prolonged and repeated febrile and afebrile generalised or unilateral convulsive seizures, as well as interictal myoclonus and ataxia. Nocturnal generalised tonic-clonic seizures predominate.There is mild to severe intellectual disability, and variable motor abnormalities.
EEG at onset may be normal. However, later in the course of the disease EEG is abnormal.Massive myoclonic jerks are associated with bursts of irregular spike and waves, or polyspike and waves, on the EEG.Interictal EEG may be normal in the first year of life, but gradually becomes abnormal with slowing of background.Sleep features are usually maintained.One third of the children show de novo mutations of the SCN1A gene. [24]
Benign familial infantile seizures
A clinical entity characterised by focal seizures with or without secondary generalisation, occurring in clusters.Onset between 4 months and 8 months of age. Psychomotor development is normal, and seizures usually resolve within the first year of life.Mode of inheritance is autosomal dominant. [25]
The interictal EEG is normal. The ictal EEG shows diffuse discharge with onset in the central occipital region.Laboratory, radiological, and neurological findings are normal.A genetically heterogenous condition with loci mapped to chromosomes 16 and 19.
Benign neonatal sleep myoclonus
A non-epileptic condition characterised by myoclonic jerks that occur only during sleep and stop abruptly when the child is aroused.It is frequently confused with epileptic seizures during infancy.It resolves by 1 year of life. [26]
EEG is normal.
Gastrointestinal reflux
Reflux may mimic seizures, especially in the infant and neonate.Sandifer's syndrome is a variant that presents with neck or trunk twisting.
EEG is normal.pH probe studies demonstrate abnormally low pH.
Benign myoclonus of early infancy
Syndrome similar to infantile spasms with features of flexion spasm in early infancy.The series of spasms can occur during wakefulness, during sleep, and immediately after awakening.There is no mental and psychomotor involvement and infants have a normal development.
EEG is normal during wakefulness and sleep.

Infectious mononucleosis

Group A streptococcal pharyngitis
Epstein Barr virus (EBV) pharyngitis may be clinically indistinguishable from streptococcal pharyngitis.
Throat culture for group A streptococcus is positive.However, 3% to 30% of patients with IM may have positive throat culture for group A streptococcus, and differentiating carrier state from true streptococcal infection in patients with IM can be challenging. [37] [38] If EBV is strongly suspected, routine throat culture is not necessary.Antibiotics should be used only for uncommon cases of true concomitant streptococcal infection, after the throat culture confirmation of group A streptococci. Unnecessary use of ampicillin, amoxicillin, or beta-lactams frequently results in a rash in patients with IM.
Hepatitis A
Presents with fever, abdominal pain, jaundice, and malaise. Hepatomegaly is common. Eyelid oedema, pharyngitis, adenopathy, splenomegaly, and atypical lymphocytosis are usually absent with hepatitis A.
Aminotransferases (ALT/AST) elevated 10 fold or greater.Positive hepatitis A serology.Heterophile antibody negative.
Acute HIV infection
Early HIV infection can cause an acute illness with fever, malaise, lymphadenopathy, and maculopapular, blanching rash.Less prominent pharyngitis; more frequent rash; presence of diarrhoea with HIV.
Plasma viral load test (PVL) is positive.ELISA HIV test may be positive. However, often negative in the acute infection, and IM may cause false-positive result.
Adenovirus
Coryza, cough, pneumonia, conjunctivitis, diarrhoea are typically present in adenovirus infection.
Nasopharyngeal swab for culture of respiratory viruses is positive for adenovirus.
Human herpes virus-6
Common febrile illness of early childhood; disease course is characterized by 3 to 5 days of fever followed by a typical exanthem of rose-pink macules and papules that appear with defervescence on the trunk, neck, proximal extremities, and occasionally on the face . Prolonged febrile mononucleosis syndrome in adults. Prolonged febrile mononucleosis syndrome in adults.
Anti-HHV-6 IgM and IgG positive.
Cytomegalovirus infection
Infection in healthy individuals can be asymptomatic or symptoms may resemble mononucleosis syndrome (fever, malaise, pharyngitis). Physical exam may show lymphadenopathy and splenomegaly.
Aminotransferases or alkaline phosphatase are frequently elevated; CMV serology is the most accessible test in the community setting and often sufficient for diagnosis in immunocompetent individuals. Viral culture, PCR, or pp65 antigen detection may be used if available.
Herpes simplex virus-1
Exudative pharyngitis, gingivostomatitis, odynophagia.
Viral throat culture, PCR.

Infective endocarditis

Rheumatic fever
Patients with rheumatic heart disease may present very similarly with predominantly constitutional symptoms. Jones criteria are diagnostic and consist of carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules, and evidence of preceding streptococcal infection. [18]
Positive antistreptolysin O antibodies or anti-DNAase B.Echocardiogram may demonstrate evidence of CHF with globalised carditis, but generally lacks specific vegetations seen with infective endocarditis (IE).Endomyocardial biopsy will reveal pathognomonic Aschoff bodies, which are persistent local inflammatory lesions.
Atrial myxoma
Patients may present with constitutional symptoms secondary to cytokine release or may have systemic disease secondary to embolic phenomenon.Often patients will describe waxing and waning symptoms as opposed to the subacute progressive nature of IE.
CXR may demonstrate characteristic calcifications within the heart or a small atrium.Echocardiography with subsequent histological examination is the most specific and sensitive test for diagnosis of atrial myxoma.
Libman-Sacks endocarditis
Patients are commonly asymptomatic, and have history suggestive of a diagnosis of SLE.Patients with a positive antiphospholipid antibody may report repeated miscarriages, venous thrombosis, or thrombocytopenia.
Often will have positive auto-antibody profile including ANA, antidouble stranded DNA antibody (anti-dsDNA), and anticardiolipin antibody with associated valvular disease.Immunohistochemical staining will demonstrate a lack of neutrophil and characteristic anti-inflammatory response seen in IE.
Non-bacterial thrombotic endocarditis (NBTE)
Most common tumours producing NBTE are pancreatic, lung, and colon, so patients may report signs and symptoms consistent with those underlying conditions.Also may report symptoms of underlying hypercoagulable state such as recurrent DVT, accelerated atherosclerosis, pre-mature CAD, MI, or stroke. [19]
Patients often have underlying carcinomas or hypercoagulable state, so CT scan of chest, abdomen and pelvis may demonstrate a primary tumour responsible for underlying pathology, which is thought to be secondary to mucin production with subsequent embolic phenomenon.

Infertility in women

Male factor infertility
Often no differentiating signs or symptoms. It is important to note that approximately 18.5% of cases of infertility can be attributed to a male factor, and 18.4% of cases attributed to combined male and female aetiologies. [5] Male factor is often present even when a female factor is identified.
Semen analysis of male partner.

Influenza infection

Bacterial pneumonia
In addition to cough and fever there may be pleuritic chest pain, dyspnoea, and sputum production that may be mucopurulent.
CXR: common finding is a lobar consolidation.Blood culture: positive for infecting organism.Sputum culture: growth of infecting organism.
Respiratory syncytial virus (RSV) infection
Most common cause of lower respiratory tract infection in children <1 year. [61] [62]Also a significant and often unrecognised cause of lower respiratory tract infection in both older and immunosuppressed patients. [63]Gives rise to upper and lower respiratory symptoms that peak in 3 to 5 days and resolve within 7 to 10 days.Characterised by seasonal outbreaks. In the northern hemisphere, these usually occur from November to April, with a peak in January or February. In the southern hemisphere, wintertime outbreaks occur from May to September, with a peak in May, June, or July. In tropical and semi-tropical climates, the seasonal outbreaks are usually associated with the rainy season. [64]
Rapid assays utilising antigen capture technology that can be performed in less than 30 minutes are now available. The sensitivity and specificity of most of these tests exceed 90%, and they are a mainstay of the diagnostic algorithm in most clinical laboratories, as the identification by culture can take from 4 days to 2 weeks. [62]
Parainfluenza virus infection (PIV)
An important respiratory pathogen in adults and children; the second most common cause, after RSV, of acute lower respiratory tract infections in infants and young children. [65]In adults, generally causes mild upper respiratory tract infections, but can induce life-threatening lower respiratory tract infections in immunocompromised patients. [66]The seasonal patterns of PIV infection in the US have changed over the past few decades. After 1962, PIV-1 and PIV-2 began to present in epidemics, and currently appear every 2 years in the autumn. In comparison, PIV-3 occurs in annual spring epidemics, whereas seasonal patterns of PIV-4 infections have been difficult to establish, since the disease is usually mild and the virus is difficult to detect. In developing and tropical countries, parainfluenza viruses do not show seasonal variations. [67]
Culture of PIV from the nasopharynx or lower respiratory tract remains the definitive test for diagnosis. [68]Rapid antigen detection by immunofluorescence and EIA is available, with reported sensitivities of 75% to 95%. [69]Serological testing can also be performed, but is time-consuming.Multiplex PCR assays have become available that permit detection of a number of respiratory viruses with reported sensitivities of 95% to 100%, with excellent specificity. [70]

Inguinal hernia

Undescended testis
Presence of a groin mass. Underdeveloped hemiscrotum with absent testis on the affected side.Inguinal hernia is associated with fully developed hemiscrotum and the bulge in the groin is associated with expansible cough impulse.
Groin ultrasound scan is able to detect an undescended testis from an inguinal hernia. Other tests such as CT scan of the mass and MRI scan, are equally sensitive.
Lymphadenopathy
An enlarged lymph node may be associated with a history of trauma, infection or malignancy. It is not associated with cough impulse. Lymphadenopathy, like strangulated hernia, may be tender but, unlike hernia, one can get above the mass and it may be mobile.
Groin ultrasound scan may show internal echo on sonogram in cases of lymphadenopathy, whereas hernia may show abnormal ballooning of the anteroposterior diameter of the inguinal canal.
Femoral hernia
Distinguishing between femoral and inguinal hernia is difficult. Femoral hernias are more common in females and more prone to strangulation. It is often preceded by a history of recent weight loss.
Anatomical localisation by ultrasound, CT or MRI will show a femoral hernia lateral and below the pubic tubercle. An inguinal hernia is superomedial to the pubic tubercle.
Femoral aneurysm
Differentiated from inguinal hernia by the presence of pulsatile mass.
Femoral artery aneurysm may be distinguished from inguinal hernia by a Doppler or Duplex scan that reveals blood flow.
Psoas abscess
May present with back pain and fever. Recent history of foreign travel or contact with someone with chronic cough, weight loss and night sweats are not uncommon.
MRI and CT scan will show an abscess as an inflammatory mass within the psoas muscle.
Saphena varix
Dilated great saphenous vein close to the saphenofemoral junction because of incompetent saphenofemoral valve. Often, there are signs elsewhere of varicosity. Typically it is soft, compressible and, like inguinal hernia, it disappears on lying supine. It is also associated with a cough impulse and a fluid thrill.
Doppler or Duplex scan will show blood flow.
Vaginal hydrocele
This is the most common form of primary hydrocele. Although rare in children, it is common in middle age to old age. In this, the hydrocele surrounds the testicle and is not in communication with the peritoneal cavity. Testis and epididymis are not easily defined. The ability to get above the swelling is the key differentiating feature. Often, it transilluminates brilliantly.
Investigation is usually not required.
Encysted hydrocele of the spermatic cord
This is a rare form of hydrocele in which the hydrocele that is separated from the peritoneal cavity and testis is associated with the spermatic cord. Its presence may be confirmed clinically by pulling down on the testicle and seeing the lump follow.
Investigation is usually not required.
Lipoma of the spermatic cord
Lipoma of the cord is often difficult to distinguish clinically from hernia. Clinically, it is soft to touch.
Ultrasound shows an echogenic solid mass.
Spermatocele
Cyst attached to the head of the epididymis. Smooth and able to get above it on examination. Often transilluminates.
Investigation is usually not required.
Hydrocele of canal of Nuck
In females, if the processus vaginalis remains patent, it extends into the labium majus and is known as the canal of Nuck. It may easily be confused with inguinal hernia.
Ultrasound shows a well-defined, cystic, hypoechogenic mass.

Inhalation injury

Asthma
History of longstanding episodes of cough, wheezing, and/or dyspnoea.Absence of obvious inhalation exposure.May co-exist with inhalation injury.
Airflow obstruction documented prior to inhalation exposure.
COPD
History of chronic cough, sputum production, and/or dyspnoea.Absence of obvious inhalation exposure.Evidence of chronic pulmonary disease (barrel chest, clubbing).May co-exist with inhalation injury.
CXR demonstrates lung hyperinflation and flattened diaphragm.Pulmonary function testing reveals large lung volumes (total lung capacity, functional reserve capacity).
Cardiogenic oedema
History of congestive heart failure (CHF), or new-onset chest pain or palpitations.Examination shows non-pulmonary evidence of CHF (elevated jugular venous pressure, extremity oedema, ascites).May co-exist with inhalation injury.
ECG, cardiac enzymes, or echocardiography suggestive of ischaemia or heart failure.
Head trauma
History of witnessed trauma or fall.Examination demonstrates soft tissue injury, focal deficit on neurological examination.May co-exist with inhalation injury.
Head CT scan: may show signs of head trauma.Carboxyhaemoglobin (CO-Hb) level: normal if no co-existent inhalation injury.
Intoxication
History of intoxicant use.Constellation of symptoms suggestive of specific intoxication.May co-exist with inhalation injury.
Urine toxicology screen: positive for drug use.Serum ethanol level: positive for ethanol use.Osmolar gap: increased in alcohol intoxication.

Inpatient glycaemic management

Transient hyperglycaemia (e.g., from stress, corticosteroids, parenteral/enteral nutrition)
In corticosteroid-induced hyperglycaemia, there is a clear hx of corticosteroid use (including possible intramuscular injections of corticosteroids).
HbA1c normal (reflecting normal blood glucose before the illness).
Type 1 diabetes mellitus
May have a genetic predisposition and usually present at young age (5-15 years old). May have hx of polyuria, polydipsia, and unintentional weight loss.
HbA1c ≥6.5% orFasting plasma glucose: ≥7 mmol/L (≥126 mg/dL) orOral glucose tolerance test: 2-hour plasma glucose ≥11.1 mmol/L (≥200 mg/dL).Random blood sugar ≥11.1 mmol/L (≥200 mg/dL).Plasma and urine ketones: elevated in ketoacidosis.Fasting C-peptide: low or undetectable, may also be normal.Anti-glutamic acid decarboxylase (GAD) antibodies, islet cell antibodies (ICA), insulinoma-associated protein-2 (IA-2): positive. [1]
Type 2 diabetes mellitus
Usually older age. May have FHx of type 2 diabetes. Higher risk in black, Latino, and Native American people.May have features of metabolic syndrome (hypertension, obesity, hyperlipidaemia).Polyuria, polydipsia, and unintentional weight loss may occur.May have indication of insulin resistance (e.g., acanthosis nigricans or polycystic ovarian syndrome). [1]
HbA1c ≥6.5% orFasting plasma glucose: ≥7 mmol/L (≥126 mg/dL) orOral glucose tolerance test: 2-hour plasma glucose ≥11.1 mmol/L (≥200 mg/dL) orRandom blood sugar ≥11.1 mmol/L (≥200 mg/dL) accompanied by symptoms.All tests must be repeated in the absence of unequivocal hyperglycaemia.Fasting C-peptide: detectable. [1]
Pre-diabetes
Risk factors and hx similar to those of type 2 diabetes.
Impaired fasting glucose: fasting plasma glucose 5.55 mmol/L to 7 mmol/L (100-125 mg/dL).Impaired glucose tolerance: oral glucose tolerance test 2-hour plasma glucose 7.8 mmol/L to 11 mmol/L (140-199 mg/dL).HbA1c of 5.7% to 6.4% indicates pre-diabetes or high risk of future diabetes. [1]

Insect bites and stings

Cellulitis
Hx of previous episodes of cellulitis; ulcer or wound; dermatosis; tinea pedis interdigitalis; lymphedoema; venous insufficiency or chronic leg oedema.
FBC: elevated WBC.Blood cultures: positive.Purulent focus culture: positive.
Periorbital and orbital cellulitis
Hx of previous sinus infection, lack of Haemophilus influenzae type b vaccination; stye or chalazion; recent eye trauma.
FBC: elevated WBC.Blood cultures: positive.Microbiology eye swab: positive.
Abscess
Red, tender, fluctuant mass; fever; purulent drainage.
Incision and drainage yields pus/necrotic material. Culture can identify infectious organism.
Necrotising fasciitis
Hx of immunosuppression due to chronic illness (e.g., diabetes mellitus, alcoholism); cutaneous trauma or ulcerative skin conditions; varicella zoster infections; hospitalisation.
FBC: elevated WBC.Urea and creatinine: elevated.Sodium: normal or reduced.Serum creatinine phosphokinase: elevated.Blood cultures: positive.ABG analysis: hypoxaemia and acidosis.
Folliculitis
Recent hx of immersion in spa water; darkly pigmented male with curly hair; recent hx of shaving; umbilicated flesh-coloured papules.
Gram stain: gram-positive cocci typical of Staphylococcus aureus infection.Potassium hydroxide preparation: presence of hyphal forms suggestive of dermatophyte infection.
Basal cell carcinoma
Hx of UV radiation, sun exposure, x-ray exposure, arsenic exposure, xeroderma pigmentosa, Gorlin-Goltz syndrome, or transplant.Papules with associated telangiectasias; plaques, nodules, and tumours with rolled borders; small crusts and non-healing wounds; non-healing scabs; pearly papules or plaques. Unlike bites and stings, these lesions do not appear acutely.
Shave/punch biopsy: growth of nest(s) of varying size and shape.
Squamous cell carcinoma of the skin
Hx of UV exposure, older age, immunosuppression, fair skin, human papillomavirus, hereditary skin conditions, exposure to ionising radiation/arsenic/tar, actinic keratosis, male sex. Unlike bites and stings, these lesions do not appear acutely.Erythematous papules or plaques; thin flesh-coloured or erythematous plaques/dome-shaped nodules; exophytic, fungating verrucous nodules or plaques.
Biopsy: keratinocyte atypia.
Kaposi's sarcoma
HIV infection; immunosuppressive therapy; transplantation, Central African ethnicity (e.g., from Uganda, Malawi, Zambia, Zimbabwe); human herpesvirus-8 infection.Skin lesions may be multifocal, asymmetrically distributed, non-pruritic, varying in size (ranging from several millimetres to centimetres in diameter) and colour (pink, red, purple, brown, or blue), papular, nodular, plaque-like, bullous-like, fungating with skin ulceration and secondary infection, indurated (woody), or hyperkeratotic.
HIV test: positive.Biopsy: characteristic vascular lesion.
Local trauma
Hx of trauma.
X-ray: may show evidence of trauma.
Intra-abdominal processes (differential of black widow spider bite)
Abdominal tenderness with guarding or rebound tenderness. Bowel sounds may be absent.May have risk factors for mesenteric ischaemia, gastroenteritis, bowel obstruction, etc.
X-ray: may show dilated bowel loops.FBC may be elevated in infectious process. Lactate may be elevated in mesenteric ischaemia.Ultrasound/CT/MRI may show pathology.
Compartment syndrome of the abdomen
Hx of excessive fluid resuscitation (>5 L in 24 hours), massive blood transfusion (>10 units in 24 hours), recent abdominal infection (especially peritonitis), haemoperitoneum, ileus, abdominal distention, oliguria.
Trans-bladder measurement of intra-abdominal pressure: elevated.ABG analysis: metabolic acidosis or mixed metabolic and respiratory acidosis.
Compartment syndrome of extremities
Hx of trauma, bleeding disorder, compression support, thermal injury, intravenous infusion, venous obstruction, sports playing. Loss of muscle function, pain, pressure (tightness), paraesthesia, pulselessness, pallor, paralysis.
Compartment pressure: differential pressure ≤20 mmHg.Serum creatinine kinase: elevated.Urine myoglobin: elevated.
Muscle spasm
Episodic occurrence. Hx of muscle strain or trauma.
Clinical diagnosis.
Migraine
FHx of migraine. Risk factors include childhood motion sickness; caffeine intake; high altitude; female gender; menstruation; divorced, widowed, or separated; obesity; habitual snoring; stressful life events; overuse of headache medications; lack of sleep.
Clinical diagnosis.
Subarachnoid haemorrhage
Hx of hypertension, smoking, or autosomal dominant polycystic kidney disease; FHx of subarachnoid haemorrhage; photophobia; altered mental status.
CT head: hyper-dense areas in the basal cisterns, major fissures and sulci.Lumbar puncture: bloody CSF (xanthochromia).
Acute myocardial infarction
Cardiac risk factors, chest pain, SOB, nausea, diaphoresis, eliciting factors.
ECG: ischaemic changes.Cardiac enzymes: positive.
Toxic plant ingestion
Hx of recent ingestion of plant matter.
Clinical diagnosis.
Organophosphate poisoning
Hx of recent ingestion of insecticides; distinctive odour; incontinence; visual disturbances.
Atropine therapeutic trial: lack of anticholinergic effects.Plasma cholinesterase: reduced activity.
Shock
May be cardiogenic, septic, or hypovolaemic.Hx of recent MI, recent surgery or immobilisation, severe infection, or haemorrhage.
Lactate >2 mmol/L (>18 mg/dL) is suggestive of tissue hypoperfusion.ABG analysis: pH <7.35 indicates acidosis.
Acute asthma
Hx of viral infection, exposure to cigarette smoke, exposure to allergens, atopic eczema, environmental irritants, GORD, use of oral corticosteroids, or non-compliance to asthma medication.
PEFR: <60% of predicted value if severe.
Acute COPD
Hx of bacterial infection; viral infection; exposure to pollutants; change in weather.
CXR: hyper-inflation, flattened diaphragm, bullae, and a small vertical heart.ABG analysis: respiratory acidosis and compensatory metabolic alkalosis.
Foreign body aspiration
Sudden-onset stridor or choking; hx of foreign body in mouth (especially in young children).
CXR may show air-trapping and hyper-expanded lung field.
Viral syndrome
Fever, chills, myalgias, upper respiratory infection symptoms, GI symptoms.
Clinical diagnosis.
Drug reaction
Usually diffuse rash developing after beginning new medication.
Symptom improvement after removal of drug.
Atopy
Recurrent sensitivity reactions following certain exposures.
Allergy testing: positive.
Chemical exposure or sensitivity
Hx of recent exposure.
Clinical diagnosis.

Insomnia

Restless legs syndrome (RLS)
Difficulty in sleeping may occur due to discomfort or irresistible movements of the legs.
No differentiating tests. Diagnosis is based on clinical history.
Periodic limb movement disorder (PLMD)
PLMD is characterised by rhythmic movements of the limbs during sleep, which often disturbs sleep.
Polysomnography and EMG results help to differentiate insomnia from PLMD.
Obstructive sleep apnoea (OSA)
OSA is a sleep-related breathing disorder characterised by reductions in airflow during sleep.
Polysomnography with measures of nasal/oral airflow, respiratory effort, oxygen saturation, body position, and snoring sounds.
Circadian rhythm disorders
Circadian rhythm disorders are disorders of sleep timing, such as advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS).
Sleep history.
Short sleeper
Habitual duration of sleep <5 hours nightly with normal sleep onset, continuity, and quality, and not associated with daytime impairment.
Sleep history.
Poor sleep hygiene
Sleep disturbance due to behaviours that are not conducive to sleep (caffeine, alcohol use, or irregular sleep habits).
Sleep history.

Interstitial cystitis

Endometriosis
High abdominal and cervical tenderness.Urethral pain.Dysfunctional menstrual bleeding.Absence of anterior vaginal wall tenderness over urethra or bladder neck on bi-manual examination. [26]
Laparoscopy demonstrates sites of ectopic endometrial implantation.
Irritable bowel syndrome (IBS)
Faecal urgency and frequency.Excessive straining on defaecation.Alternating constipation and diarrhoea.Pain on digital rectal examination.Almost 50% of patients may have symptoms related to IBS. [27] Symptoms/signs may be similar due to overlapping spinal cord innervation.
Colonoscopy is usually normal, but mucosal inflammation or ulceration suggests IBS.
Urinary tract infection
Fever and haematuria.Absence of pain with palpation of levator ani (pelvic diaphragm) on bi-manual examination.May co-exist with IC/painful bladder syndrome (PBS).
Positive urine cultures.Positive response to antibiotic therapy.
Overactive bladder
Absence of pain with palpation of the urethra, bladder neck, and levator ani (pelvic diaphragm) on bi-manual examination.
Potassium sensitivity test is negative.No glomerulations and/or Hunner's ulcers with cystoscopic hydro-distention.

Intestinal malrotation

Duodenal atresia/web
Duodenal atresia is usually not associated with abdominal pain, physiological perturbation, or metabolic acidosis. Any of these signs should press urgent action towards diagnosis and treatment of volvulus.
On plain x-ray in a newborn with bilious vomiting, the presence of bowel gas beyond the duodenum suggests either midgut volvulus or type 1 duodenal atresia; therefore, an upper GI series should be done to differentiate between them.
Intussusception
The incidence of intussusception increases sharply at 5 months when volvulus is beginning to decrease in incidence.Bilious vomiting is delayed or secondary if present at all in the presentation of intussusception as opposed to volvulus.Intussusception is typically distinguished by periods of sudden abdominal pain followed by complete cessation. These continue to return as equally sharp in waves, until the intussusception is reduced.
Ultrasound identifies intussusception in most cases.Contrast enema (with air or barium) is thereafter used to confirm the diagnosis and reduce the intussusceptum.
Gastro-oesophageal reflux
Malrotation without volvulus may cause intermittent non-bilious vomiting that appears identical to reflux, and the two cannot be distinguished by history or physical examination.
Upper GI contrast series definitively clarifies malrotation.
Non-specific symptoms
It is important to consider that malrotation without volvulus is diagnosed for a wide variety of complaints that lead to a contrast study, including diarrhoea, constipation, anorexia, irritability, apnoea, lethargy, failure to thrive, blood in stool, and fever. [11]
Upper GI contrast series definitively clarifies malrotation.

Intra-abdominal abscess

Loculated intra-abdominal haematoma
A loculated haematoma can be very challenging to differentiate from an IAA.
Haemoperitoneum is usually accompanied by a drop in haematocrit.Fluid sampling and culture is usually diagnostic. Measurement of fluid density by CT scan may be helpful.
Pancreatic pseudocyst
Usually accompanied by a recent history of pancreatitis. A challenging part in the work-up of a pancreatic pseudocyst is the exclusion of an infection. High-grade fever is unlikely in pancreatitis.
Air-fluid level on CT scan will help identify an infected pancreatic pseudocyst. Fluid sampling usually confirms the diagnosis.Absence of debris on CT scan is helpful to exclude an abscess.
Diverticular or appendiceal phlegmon
A phlegmon is an inflammatory mass with some associated exudates, and therefore not an actual abscess. Phlegmon may become an abscess if not treated. Both may have the same clinical picture.
Sometimes very hard to differentiate from an abscess. CT scan may be helpful.
Intra-abdominal serum or lymph collection
Other fluids that collect in the peritoneal cavity are lymph or serum (seroma). Sometimes very hard to differentiate from an abscess.
CT scan may be helpful to evaluate the character of the fluid in the collection. Fluid sampling and culture is usually diagnostic.
Normal post-operative changes or post-operative fluid collections
Differentiation of an early IAA from normal post-operative changes and fluid collections can be challenging. Most post-operative fluid collections are not infected and resolve spontaneously. However, infected fluid collections are associated with significant morbidity and mortality, and require percutaneous or surgical drainage.
Imaging features that indicate infection include the presence of gas where none was seen previously, the development of a discrete abscess wall, and rim-shaped enhancement in the abscess wall, with either single- or double-ring signs.

Intussusception

Appendicitis
In appendicitis, rectal bleeding is not present.Patients with appendicitis may describe abdominal pain that has migrated from a periumbilical position to the right lower quadrant.The abdominal pain of intussusception is more colicky than the abdominal pain that is commonly described in appendicitis.
The findings of an intussusception mass and 'target sign' or other characteristic signs will be absent on ultrasound examination if appendicitis in present. Ultrasound has value in the detection of appendicitis, although clinical experience dictates that the use of ultrasound is highly operator-dependent, and that the false-negative rate is quite high in young children, particularly those in the age group for intussusception.CT may be helpful in identifying appendicitis.
Gastroenteritis
Gastroenteritis involves episodes of vomiting that are typically non-bilious, often in association with anorexia, fever, lethargy, and diarrhoea.Rectal bleeding is absent in gastroenteritis, except in the presence of invasive organisms such as Salmonella or Shigella.
The findings of an intussusception mass and characteristic signs will be absent on ultrasound examination if an infant presents with gastroenteritis.Plain abdominal films may show dilated small- and large-bowel loops.
UTI
UTI may present with fever, foul-smelling urine, lethargy, frequent urination, painful urination, anorexia, and vomiting, and in fact may be easily confused with intussusception or gastroenteritis.
Plain films may reveal an ileus pattern; CT may show evidence of pyelonephritis in advanced cases; ultrasound may be normal.Urinalysis and culture establish the diagnosis.
Pyloric stenosis
Typically develops in a 3- to 6-week-old infant, but may be seen between 2 and 12 weeks.Presents with projectile non-bilious vomiting after feeding.An upper abdominal mass (olive) may be detected by palpation.
Abdominal ultrasound shows a pyloric channel length >17 mm and pyloric muscle thickness >4 mm.

Iron deficiency anaemia

Anaemia of chronic disease
On FBC, in 80% of cases, anaemia of chronic disease is normocytic and normochromic. However, in 20% of cases it can present as a microcytic, hypochromic anaemia much like IDA.
FBC and peripheral smear: anaemia, hypochromia, microcytosis, anisocytosis, and poikilocytosis are less pronounced than in IDA.Ferritin is often elevated in patients with anaemia of chronic disease. [37]Anaemia of chronic disease has a normal transferrin receptor assay. [37]
Disorders of globin synthesis (thalassaemias, haemoglobin E, haemoglobin C, unstable haemoglobins)
This is a potpourri of disorders and often requires a haematologist to sort them out. Patients with severe thalassaemia are usually transfusion dependent from childhood and therefore diagnosed early. Patients with thalassaemia minor may not be diagnosed until adulthood.Haemoglobin electrophoresis may help distinguish these disorders but can be normal.
FBC: often more severe microcytosis than expected for the degree of anaemia. Haemoglobin will never be normal. In thalassaemia, red cell distribution width is usually normal.Peripheral smear: more pronounced basophilic stippling and target cells.Haemoglobin electrophoresis: raised Hb A2 level is a common beta-thalassaemia trait.
Disorders of porphyrin and haem synthesis
This is a collection of disorders characterised by defective synthesis of porphyrin and haem. An enzymatic defect leads to an accumulation of the substrate in the red cells and plasma and is therefore excreted in the urine and/or stool.Some of these disorders are accompanied by neurological disorders and/or photosensitivity. They often have a positive family history.
Testing for most of these disorders is not readily available and requires referral to a haematologist and possible research centres.
Sideroblastic anaemias
Alcoholism can be a cause of a reversible sideroblastic anaemia. Hepatosplenomegaly is found in one third to one half of patients with sideroblastic anaemia and is not present in IDA. [15]Peripheral smear and bone marrow biopsy can help distinguish this from IDA, although erythrocyte dimorphism is also seen in partially treated IDA.
Peripheral smear: erythrocyte dimorphism (hypochromic, microcytic population mixed with normal population).Presence of the occasional heavily stippled, hypochromic cell. [15]Bone marrow biopsy: ringed sideroblasts seen because of accumulation of iron in the mitochondria.
Lead intoxication
Patients may have a history of risk factors for lead exposure such as occupational exposures (exposure to lead paint) or distillation of moonshine alcohol.
Lead level and free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) can be tested. Lead level is increased. Increased FEP or ZPP can reflect exposure to lead in previous 3 months (the typical life span of a red cell).
Atransferrinaemia
This very rare disorder is characterised by low plasma iron concentration secondary to a lack of transferrin, which normally acts as a specific iron transport protein.Transferrin can be given to correct the disorder. [15]
Serum and bone marrow iron levels: low as they are in IDA, but, unlike in IDA, total iron-binding capacity will also be low. [15]
Antibodies against the transferrin receptor
This is very rare and only reported as case reports. Clinically these patients would resemble patients with IDA.
FBC: hypochromic, microcytic anaemia.Bone marrow biopsy: devoid of iron.Iron profile: increased serum iron concentration, normal serum ferritin level.FEP: dramatically increased. [15]
Aluminium intoxication
This occurs primarily in haemodialysis patients if the public water supply is used as a source of water for dialysis. This can be avoided with the use of deionised water and can be reversed with the use of a deferoxamine chelator. [15]
Erythrocyte aluminium levels would be increased. [15]
Copper deficiency (hereditary aceruloplasminaemia)
Patients will often have neurological abnormalities. [50]
Patients will have a microcytic anaemia, increased ferritin, and no serum ceruloplasmin. [50]
Gallium administration
Gallium binds to transferrin and inhibits cellular iron uptake. Patients would have a history of gallium infusion.
Microcytic hypochromic anaemia was noted in patients treated with gallium in a phase II chemotherapy trial. [15]

Irritable bowel syndrome

Crohn's disease
May present with fatigue, diarrhoea, abdominal pain, weight loss, fever and rectal bleeding. Other signs may include presence of oral ulcers, perianal skin tags, fistulae, abscesses and sinus tracts; abdominal exam may reveal a palpable mass in the ileocaecal area; no mass present on digital rectal examination.
Stool culture, microscopy and antigen testing: negative.Upper GI and small bowel series: oedema and ulceration of the mucosa with luminal narrowing and strictures. CT/MRI abdomen: skip lesions, bowel wall thickening, surrounding inflammation, abscess, fistulae.Colonoscopy: aphthous ulcers, hyperaemia, oedema, cobblestoning, skip lesions.
Ulcerative colitis
May present with bloody diarrhoea, hx lower abdominal pain, faecal urgency, presence of extraintestinal manifestations (e.g., erythema nodosum, acute arthropathy), hx of primary sclerosing cholangitis. No mass present on digital rectal examination.
Stool culture, microscopy and antigen testing: negative.Histology: continuous distal disease, mucin depletion, basal plasmacytosis, diffuse mucosal atrophy, absence of granulomata and anal sparing.Colonoscopy: rectal involvement, continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, normal terminal ileum (or mild 'backwash' ileitis in pancolitis).
Lymphocytic and collagenous colitis
The patient with lymphocytic or collagenous colitis will have soft to watery diarrhoea that often is not associated with pain and tends not to be episodic. Physical examination is normal.
Blood chemistry: may reveal azotaemia and hypokalaemia.Endoscopy and histology: although the colon mucosa may look normal endoscopically, there will be abnormal changes histologically on colon biopsies.
Coeliac disease
Patients with coeliac disease usually have weight loss. The physical examination is usually negative. Some patients with coeliac disease will have early osteoporosis.
Basic laboratory tests: may show iron-deficiency anaemia, hypocalcaemia, or a prolonged prothrombin time, although many patients with coeliac disease will have no routine laboratory abnormalities.Anti-endomysial antibodies and tissue transglutaminase antibodies may be detected in coeliac disease. [12] Small bowel biopsy will be abnormal with partial villous atrophy in coeliac disease.
Colon cancer
Colon cancer can sometimes cause a change in bowel habits with either constipation or more frequent, smaller calibre stools. Some, but not all, colon cancer patients will have blood in their stool, and a rectal cancer may be palpable on rectal examination.
FBC: iron-deficiency anaemia may be present.Endoscopy: will demonstrate malignant growth; colon cancer can be diagnosed by colonoscopy, whereas cancers of the rectum, sigmoid, and lower descending colon can be seen with flexible sigmoidoscopy.Barium enema: although less sensitive than endoscopy, many colon cancers can be seen on air-contrast barium enema.CT colography is accurate for colon neoplasms but is not yet widely available.
Bowel infections
Most bacterial and viral infections in immunocompetent patients are acute. The parasite Giardia lamblia can be associated with diarrhoea, nausea, and bloating.
Stool examination for ova and parasites can be used for screening. Multiple stools should be examined.Serum Giardia antigen is accurate for diagnosing Giardia lamblia.

Ischaemic bowel disease

Infectious colitis
May have similar clinical features.
Colonoscopy will demonstrate if ischaemia is present.Stool cultures may reveal causative organism.CT may show marked thickening of colon with Clostridium difficile.
Ulcerative colitis
Form of inflammatory bowel disease that affects the rectum and extends proximally. Characterised by diffuse inflammation of the colonic mucosa and a relapsing, remitting course.Patients commonly experience bloody diarrhoea, chronic diarrhoea (or both), lower abdominal pain, faecal urgency, and extraintestinal manifestations, particularly those related to activity of the colitis.
Diagnosis requires endoscopy with biopsy and negative stool culture.
Crohn's disease
Inflammatory bowel disease that may involve the entire gastrointestinal tract.Common presenting symptoms include chronic diarrhoea, weight loss, and right lower quadrant abdominal pain mimicking acute appendicitis.
Diagnosis confirmed by colonoscopy with ileoscopy and tissue biopsy.
Diverticular disease
May have similar clinical features to ischaemic bowel disease. Fever common in diverticulitis; diarrhoea common, usually no haematochezia.
CT may demonstrate focal colonic thickening and evidence of diverticulosis and diverticulitis.
Large bowel obstruction
Obstipation may be a symptom.
In most instances, CT will demonstrate cause of obstruction, such as tumour, internal hernia, or volvulus.
Peptic ulcer disease
Pain is generally epigastric and less severe, but may be generalised abdominal discomfort. Nausea and vomiting are common. Usually symptoms are less acute.
Oesophagogastroduodenoscopy will demonstrate gastritis and ulcers.
Small bowel obstruction
Often have a history of previous abdominal surgery. Nausea, vomiting and abdominal distension are the predominant features.
X-ray studies will show air-fluid levels and dilated small bowel. CT will show dilated proximal small bowel with distal decompression, with a possible transition point.
Acute pancreatitis
May provide a history of gallstones or recent alcohol use. Pain usually focal at epigastrium and radiates to back. Usually no diarrhoea or haematochezia.
Elevated serum amylase and lipase. Abdominal ultrasound and CT demonstrate pancreatic inflammation and may show related gall bladder pathology.
Gastroenteritis
May have similar clinical features. Possible history of ill contacts. May have a significant component of nausea and vomiting. Pain is often less profound than in patients with ischaemia.
CT may demonstrate thickened loops of small bowel or mesenteric lymphadenopathy without evidence of ischaemia or infarction.

Ischaemic stroke

Intracerebral haemorrhage
No symptoms or signs reliably distinguish haemorrhagic stroke from ischaemic stroke.Haemorrhagic stroke is more often associated with reduced level of consciousness and signs of increased intracranial pressure than ischaemic stroke.
CT or MRI demonstrates haemorrhage (hyperattenuation).
Transient ischaemic attack
Transient neurological symptoms last less than 24 hours, with no evidence of acute infarct.
CT or MRI may be normal or may reveal evidence of older infarcts.
Hypertensive encephalopathy
The combination of headache, cognitive abnormalities or decreased level of consciousness, and HTN significantly above patient's baseline BP indicates hypertensive encephalopathy. Other possible signs/symptoms include visual changes or loss, or signs of increased intracranial pressure. [42]
Cerebral oedema on CT or MRI.
Hypoglycaemia
There may be a history of diabetes with use of insulin or insulin secretagogues.Decreased level of consciousness.
Low serum glucose at time of symptoms.
Complicated migraine
Repetitive history of similar events; preceding aura, headache in a marching pattern differentiates complicated migraine. [42]Stroke often presents with negative symptoms (e.g., visual loss, numbness, or weakness).Positive symptoms (e.g., marching paraesthesias, visual hallucinations, and abnormal motor manifestations) are more likely with complicated migraine.
MRI shows no evidence of infarction.
Seizure and postictal deficits
Hx seizures; witnessed seizure followed by postictal deficits: for example, drowsiness and tongue-biting. [42]Wrong-way eye deviation (i.e., gaze deviation away from the side of the brain lesion, towards the hemiparetic side) should prompt consideration of seizure but can also occur with strokes affecting the pons or thalamus.
EEG confirms evidence of seizure.MRI shows no evidence of infarction.
Conversion and somatisation disorders
Neurological signs and symptoms do not fit a vascular territory.No cranial nerve deficits.Additionally, conversion disorder displays multiple signs that are neurologically inconsistent.
MRI shows no evidence of infarction.
Wernicke's encephalopathy
Hx alcohol abuse.Irritability, confusion, and delirium common presenting features.
Decreased blood thiamine level and successful therapeutic trial of thiamine.
Brain tumour
Symptoms and signs more likely to have been on-going.May be hx cancer if metastatic lesion causing symptoms.
CT head demonstrates lesion or lesions.

Isolated CNS Relapse-ALL

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Jet lag and sleep phase disorders

Travel-related fatigue
Usually symptoms are of shorter duration than jet lag. [11]
Diagnosis is clinical.
Psychophysiological insomnia
To be considered if symptoms persist beyond the episode of jet lag.
Diagnosis is achieved using actigraphy combined with a sleep diary.

Joint dislocation

Proximal humerus fracture
There is usually shoulder and upper arm swelling and bruising.Possibility of paraesthesias or weakness in the arm.
Anteroposterior (AP) and lateral view x-rays in the scapular plane and an axillary view confirm the fracture.
Distal clavicle fracture
Pain, particularly on upper extremity movement, and swelling.After the swelling has subsided, the fracture can often be felt through the skin.
AP x-ray shows fracture.
Acromioclavicular joint separation
Pain is a common symptom of this injury and is usually severe.Evidence of traumatic injury to the shoulder, such as swelling and bruising, is also commonly found.
AP x-ray rules out fractures.If diagnosis is unclear, an x-ray taken while the patient is holding a weight in the hand may be helpful. The force of the weight accentuates any shoulder joint instability and shows the effects of the injury better.
Rotator cuff tear
Shoulder pain is the most common presenting symptom.Pain is typically aggravated by over-head activities.Patients may also complain of functional weakness, loss of motion, night pain, and pain in the deltoid region.Acute pain and weakness may be seen following traumatic rotator cuff rupture.
AP x-ray or MRI scan rules out fractures.
Soft tissue contusion of the shoulder
Tenderness, swelling, and bruising of the shoulder.
An x-ray or MRI scan rules out fractures.
Scapula fracture
Relatively rare.Most patients present after high-energy trauma.Typically, there is swelling, tenderness, crepitus, and bruising over the scapular region.
AP, lateral and axillary x-ray views of the shoulder/scapula show fracture.
Biceps tendon rupture
Some patients report a sudden pain in the anterior shoulder during activity.This acute pain, frequently described as sharp in nature, may be accompanied by an audible pop or a perceived snapping sensation.
AP and axillary x-ray views are the most useful and rule out fractures.
Distal humerus fracture
Pain occurs with palpation or movement of the shoulder or elbow.Swelling and bruising are usually present.
AP and lateral views of the humerus, as well as trans-thoracic and axillary views of the shoulder, should be adequate to visualise a fracture.
Radial head fracture
Usually presents with a history of a fall on the outstretched hand.Localised swelling, tenderness, and decreased motion to radial head.The wrist, especially the distal radioulnar joint, may be damaged simultaneously.
Most radial head injuries can be adequately assessed with standard plain x-ray of the elbow.
Coronoid fracture
Usually occurs in combination with a radial head fracture.Patients often present with a history of a fall on the outstretched hand and a deformity of the elbow.The presence of an unstable reduction of the elbow is suggestive of an associated coronoid fracture.
Radiographs of the elbow in the AP, lateral and, if required, oblique views should be obtained to ascertain clearly the extent of bony injury.
Ulnar collateral ligament injury
Medial elbow tenderness and swelling are the most notable findings.Medial elbow pain is the most common symptom in athletes who throw.
Plain x-ray or MRI scan rules out fractures.
Monteggia fracture
Depending on the type of fracture and severity, patients may experience elbow swelling, deformity, crepitus, and paraesthesia or numbness.Some patients may not have severe pain at rest, but elbow flexion and forearm rotations are limited and painful.
Views of the forearm in orthogonal planes (planes at 90° to each other) are needed with the wrist and elbow joints included.Separate radiographs of the elbow should also be obtained to assess the proximal radioulnar joint, ulnohumeral articulation, and radiocapitellar joint.
Soft tissue contusion of the knee
Patients usually state that something struck the affected knee.On physical examination, there should not be any valgus laxity on abduction stress testing.
Bony pathology can usually be distinguished from soft tissue injury with plain radiographs.
Chondromalacia patellae
Softening and fissuring of articular hyaline cartilage.Patients may report anterior knee pain, especially while climbing stairs.Compression of the patella during flexion and extension of the knee elicits crepitation and discomfort.
Over-exposed lateral x-ray of the knee.Axillary x-ray views of the knee determine which facet is involved.
Patellar tendon rupture
Palpable defect in patellar ligament.With complete tears, patient is unable to extend the knee.With partial tears, patient is able to extend the knee, but extension may not be full.
Lateral radiograph of the knee may reveal small avulsion from the inferior patellar pole.
Quadriceps tendon rupture
Usually occurs in patients over 40 years of age.Patients typically present with acute knee pain, swelling, and functional loss following a stumble, fall, or giving way of the knee.Obvious suprapatellar swelling, bruising, and tenderness are present.
Standing AP x-ray or MRI scan rules out fractures.
Medial synovial plica of the knee
Symptoms may mimic those of a torn meniscus (e.g., snapping, clicking, and medial joint line tenderness).
Standing AP x-ray or MRI scan rules out fractures.
Anterior cruciate ligament injury
Sub-luxation on twisting, turning, or pivoting. Some patients can feel it coming on, other patients are not able to feel it and may experience frequent falls due to their injury.
Standing AP x-ray or MRI scan rules out fractures.
Posterior cruciate ligament injury
History of hyper-extension mechanism or a blow to anterior aspect of the knee.Difficulty going down inclines, descending stairs, or running down hills.
Standing AP x-ray or MRI scan rules out fractures.
Medial collateral ligament injury of the knee
Sensation of side-to-side toggle with activity.Difficulty with twisting or turning.Difficulty with running or pivoting.
Standing AP x-ray or MRI scan rules out fractures.
Posterolateral knee injury
Sensation of side-to-side toggle of knee with activity.Weakness of foot and ankle that may be secondary to a concurrent common peroneal nerve neuropraxia or complete injury.
Standing AP x-ray or MRI scan rules out fractures.
Meniscal tear
Patients frequently complain of mechanical symptoms in the knees such as catching, giving way, locking, clicking, and popping.On physical examination, meniscal injuries may present with quadriceps atrophy; they often have an associated knee effusion, and tenderness localised to the joint line may be present.
Standing AP x-ray or MRI scan rules out fractures.
Osteochondral fracture of the knee
Patients have immediate pain and swelling of the knee at the time of injury.They also have significant pain with weight-bearing.The mechanism of injury usually involves a high-force, twisting injury of the knee.
Diagnosis can be confirmed by an MRI scan.
Ligament avulsions of the finger
Patients often experience diffuse pain, swelling, and tingling.
AP, lateral, and oblique radiographs of the affected digit rule out fractures.
Tendon avulsions of fingers
Patients often experience diffuse pain, swelling, and tingling.
AP, lateral, and oblique radiographs of the affected digit rule out fractures.
Mallet finger
Patients notice the inability to extend the distal joint, although full passive extension remains intact.The dorsum of the joint may be slightly tender and swollen, but often the injury is painless or nearly painless.
AP and lateral radiographs centred at the DIP joint of the affected finger are required to rule out fractures.
Gamekeeper's thumb
A weakened ability to hold objects, decreased thumb stability (catching the thumb in objects, etc.), local swelling, local pain, and bruising.
Plain x-ray or MRI scan rules out fractures.

Juvenile idiopathic arthritis

Septic arthritis
Usually presents with single joint involvement, high fevers, severe pain and/or erythematous joints.
Synovial fluid analysis demonstrates the presence of bacteria, elevated white blood cells and positive cultures.Radionucleotide bone scintigraphy shows increased uptake in the affected joint.MRI shows synovial enhancement and effusion and marrow oedema of the adjacent bone in cases of accompanying osteomyelitis. Significant synovial thickening is more likely to be associated with inflammatory arthritis.Synovial fluid may be sterile in cases where reactive effusions are present secondary to juxta-articular osteomyelitis.
Osteomyelitis
Usually presents with high fevers, severe pain and/or focal tenderness.
Synovial fluid analysis may demonstrate the presence of bacteria, elevated white blood cells and positive cultures when there is involvement of the joint. Synovial fluid may be sterile in cases where reactive effusions are present secondary to juxta-articular osteomyelitis.Radionucleotide bone scintigraphy shows increased uptake in the bone.MRI shows abnormal diffuse marrow signal which is best seen on T1-weighted MRI images. However, it should be noted that false-negative MRI results may be observed early in the course of infection.
Acute rheumatic fever
Usually presents as an acute, migratory arthritis that responds well to NSAIDs. Features include continuous fever, cardiac involvement and/or erythema marginatum rashes.
Throat cultures positive for group A streptococcus; positive rapid streptococcal antigen test and/or elevated or rising streptococcal antibody titres.
Systemic lupus erythematosus (SLE)
Usually presents with non-erosive polyarthritis, malar rashes, renal involvement and/or photosensitivity. Serositis and CNS involvement are also suggestive of SLE.
High titre ANA and other autoantibodies (such as anti ds-DNA, SS-A, SS-B, Smith, RNP) may be present.Urinalysis may be abnormal, showing blood and/or protein.Low levels of complements C3 and/or C4.FBC may show leukopenia, thrombocytopenia and (autoimmune haemolytic) anaemia.
Juvenile dermatomyositis
Usually presents with muscle weakness, muscle pain and/or characteristic rashes such as Gottron's papules, linear extensor erythema or heliotrope rash.Polyarticular non-erosive arthritis is usually present, especially in early stages of disease. The polyarthritis usually responds to treatment of the underlying myositis.
Abnormal muscle-derived enzymes such as lactose dehydrogenase, aspartate transaminase, alanine transaminase, creatinine kinase and aldolase may be present.
Kawasaki disease
Usually presents with high persistent fevers which do not normalise for several days, polymorphous rash, involvement of lips and conjunctiva, oedema of extremities and/or desquamation.
Demonstration of coronary artery enlargement or aneurysms is suggestive of Kawasaki disease.
Pigmented villonodular synovitis
Usually presents with recurrent, painless swelling in one knee, ankle or tendon sheath. Usually associated with slow, progressive destruction of cartilage with bone erosion.
Synovial fluid analysis shows blood-stained, dark brown fluid.MRI shows low signal density on T1- and T2-weighted studies.
Synovial haemangiomas
There is usually no morning stiffness and treatment with NSAIDs does not result in improvement.
MRI may show absence of synovial fluid and vascular elements and enhancement.
Osteochondritis dissecans
Usually presents with activity-related pain, occasional recurrent bland effusions and/or localised tenderness on examination.
X-rays may show sub-chondral fractures.MRI may demonstrate cartilaginous separation and can also be used in lesion staging.

Kaposi's sarcoma

Bacillary angiomatosis
Due to infection by Bartonella henselae. Red papules or nodules that mimic KS may involve the skin, soft tissue, lymph nodes, and internal organs with or without associated HIV infection.
Tissue biopsy shows lobules of capillaries with epithelioid endothelial cells, apoptotic neutrophils, and extracellular bacteria (silver stain). Lesional cells are negative for latent nuclear antigen-1 (LNA-1) of HHV-8 using immunohistochemistry. [15] [16] Microbiology studies for Bartonella micro-organisms may be helpful.
Pyogenic granuloma
Rapidly growing polypoid red mass with an epidermal collarette, often seen on the finger or lips, is unrelated to HIV infection.
Tissue biopsy shows a benign lobular capillary proliferation. Lesional cells are negative for latent nuclear antigen-1 (LNA-1) of HHV-8 using immunohistochemistry. [15] [16]
Dermatofibroma
A benign lesion most commonly involving the skin with similar appearance to the papulonodular form of KS. Varying degrees of haemorrhage and pigmentation may be seen.
Tissue biopsy shows a benign proliferation of spindle-shaped cells, many of which are reminiscent of histiocytes, together with varying amounts of collagen. Haemorrhage may be present. Lesional cells are negative for latent nuclear antigen-1 (LNA-1) of HHV-8 using immunohistochemistry. [15] [16]
Angioma
Benign vascular lesions, with/without underlying HIV infection, may mimic KS.
Tissue biopsy shows a benign vascular proliferation or malformation that is negative for HHV-8 latent nuclear antigen-1 (LNA-1) immunostaining. [15] [16]
Pigmented purpuric dermatoses
Patients present with orange-brown speckled discoloration of the lower limbs (Schamberg's disease) that is unrelated to HIV infection.
Tissue biopsy is characterised by extravasation of erythrocytes in the skin with marked haemosiderin deposition. This may mimic KS in the regressive phase. [22]
Haemangioendothelioma
Low-grade vascular neoplasm that may mimic KS, usually involving the distal extremities of young individuals. Unrelated to HHV-8 and/or HIV infection.
Histopathology of the tissue biopsy shows a vascular tumour containing endothelial cells, which may be kaposiform in appearance, with prominent intracytoplasmic lumina. Lesional cells are negative for latent nuclear antigen-1 (LNA-1) of HHV-8 using immunohistochemistry. [15] [16]
Angiosarcoma
May be more aggressive than KS with frequent recurrences that involve extensive areas of face and scalp, regional lymph nodes, lungs, and other organs. Unrelated to HHV-8 and/or HIV infection.
Tissue biopsy shows an infiltrating vascular neoplasm containing spindle-shaped to epithelioid endothelial cells with marked atypia. HHV-8 immunoreactivity is typically negative. [15] [16]
EBV-associated smooth muscle tumour
Typically young, severely immunosuppressed patients present with multi-focal benign (leiomyoma) and/or malignant (leiomyosarcoma) tumours. The most common site of involvement is the brain. [23]
Tissue biopsy shows spindle tumour cells with a smooth muscle immunophenotype that are EBV infected (EBER positive). [23]

Kawasaki disease

Systemic juvenile idiopathic arthritis (systemic JIA)
A syndrome of fever, rash, lymphadenopathy, and arthritis. These patients often present with fever of unknown origin (FUO) and occasionally have organomegaly and serositis (pericarditis, pleuritis).Iritis and subcutaneous nodules are rare.The rash is a fine, evanescent salmon pink, usually appears on the trunk, proximal extremities and, less commonly, on the face. The rash accompanies the spikes of fever and tends to disappear when the fever is down.These patients do not develop coronary artery aneurysms.Unlike with other forms of JIA, patients with systemic JIA are usually anaemic and have extremely high acute-phase markers (ESR and C-reactive protein), as is found in Kawasaki disease (KD).
Presence of a positive rheumatoid factor (RF) or antinuclear antibody (ANA) test is a rare occurrence.
Scarlet fever
An acute febrile illness caused by group A streptococcus.The patients usually have evidence of upper respiratory tract infection, mostly pharyngitis, accompanied by a diffuse, fine papular erythematous rash that appears on the trunk, extremities, and face, but with circumoral pallor.Resolution of the rash is associated with desquamation that starts in the face and progresses downward.Unlike in KD, in scarlet fever lips are spared and there is no conjunctivitis or conjunctival injection.
Positive throat culture, or positive serological test for group A streptococcus (streptozyme and/or ASO), will confirm the diagnosis.
Acute rheumatic fever
An acute illness that occurs 3 to 4 weeks following the onset of group A streptococcal pharyngitis.These patients develop migratory polyarthritis and more than 50% develop carditis. [23]Less commonly, the course may be associated with chorea, subcutaneous nodules, and erythema marginatum.There is no development of coronary artery aneurysms, but untreated patients will eventually develop chronic valvular disease.
Positive throat culture or positive serological test for group A streptococcus (streptozyme and/or ASO) will confirm the diagnosis.
Toxic shock syndrome
An acute febrile illness that is associated with vomiting, diarrhoea, myalgia, strawberry tongue, and erythematous rash with subsequent desquamation.Many develop acute respiratory distress, hypotension, and shock.The disease is caused by staphylococcal or group A streptococcal infections.Unlike KD, most of these patients present at 15 to 25 years of age.
There is no diagnostic test for toxic shock syndrome. The diagnosis is based on clinical grounds.Isolation of staphylococcus or group A streptococcus serotypes that produce TSS-1 toxin will support the diagnosis.
Staphylococcal scalded skin syndrome
Caused by the staphylococcal epidermolytic toxins A and B.There is a generalised skin erythema, with development of diffuse, sterile blisters and erosions; prominent circumoral erythema; and radial crusting and fissuring around the eyes, mouth, and nose.In addition, areas of epidermis may separate in response to gentle force (Nikolsky's sign). These changes may lead to secondary infection, sepsis, and electrolyte imbalance.
Diagnosis is made on clinical grounds.Identifications of strains 55 and/or 71 of staphylococci in cultures.
Stevens-Johnson syndrome
A severe bullous form of erythema multiforme, also known as erythema multiforme major.It is characterised by high fever, pronounced constitutional symptoms, skin rash manifested by diffuse bullae, and mucosal membranes involvement.The severe explosive mucosal erosions and the widespread bullous skin lesion may differentiate this condition from KD.There is no development of coronary artery aneurysms, although these patients may benefit from high-dose intravenous immunoglobulin.
There is no diagnostic test for Stevens-Johnson syndrome. The diagnosis is on clinical grounds.
Drug reaction
History of exposure to the drug, presence of oral lesions or ulcers, periorbital oedema, and low acute-phase markers may help to distinguish it from KD.
Diagnosis is made on clinical grounds, although acute-phase markers (such as ESR and C-reactive protein) in KD are significantly higher than in an acute drug reaction.
Rocky Mountain spotted fever
A febrile illness caused by rickettsial infection (Rickettsia rickettsii). The disease is transmitted by a tick bite and characterised by fever, headaches, abdominal pain, vomiting, and diarrhoea, followed by severe myalgias.The hallmark of the disease is the rose-red blanching macular rash that appears first on the extremities, but subsequently spreads to involve the entire body, including palms and soles.After several days the rash becomes petechial or haemorrhagic, with evidence of a palpable purpura.In fulminant cases, multiorgan failure may develop, including myocarditis and renal or liver failure.
Diagnosis is made on clinical grounds, although confirmation would be achieved using indirect fluorescent antibody technique for R rickettsii.
Measles
Unlike with KD patients, measles manifestations include exudative conjunctivitis, Koplik's spots in mouth, rash that typically begins behind the ears; patients usually also appear more unwell.
Diagnosis is made on clinical grounds, although acute-phase markers (such as ESR and C-reactive protein) in KD are significantly higher, and confirmation of the viral disease would be achieved using antibody titres.

Keloid

Hypertrophic scar
No association with skin type.Always preceded by injury.On physical examination there is evidence of contraction or contractures. View imageView image
Diagnosis is clinical.Immunohistochemistry demonstrates flatter, less distinct bundles of fibres, presence of myofibroblasts, and increased density of blood vessels and cells.
Dermatofibroma
Usually no precipitating trauma but similar slow growth.Clinically, may appear as raised skin nodule, but may have subdermal extension.
Skin biopsy demonstrates proliferation of fibroblasts and dermal fibrosis.
Dermatofibrosarcoma protuberans
Clinically, the skin can appear to be normal on inspection, but is contiguous with a palpable tumor that arises from the dermis and spreads into the underlying tissue.
Diagnosis may be difficult, and when in doubt histological examination is necessary. This demonstrates neoplastic spindle-shaped nuclei.An incisional biopsy with a large sample is required.

Keratitis

Peripheral ulcerative keratitis
Non-infectious, autoimmune corneal thinning and ulceration seen in rheumatoid arthritis and some collagen vascular disease.Signs of underlying disease on examination or by history.May be accompanied by scleritis.Can become superinfected.
Negative cultures of corneal scraping.Laboratory evidence of underlying disorder (rheumatoid factor, antineutrophil cytoplasmic antibodies, etc.).
Mooren's ulcer
Idiopathic, non-infectious, unilateral or bilateral peripheral corneal thinning and ulceration not associated with collagen vascular diseases.Can become superinfected.
Negative cultures of corneal scraping.Diagnosis of exclusion.
Corneal abrasion
Epithelial defect without underlying stromal infiltrate.Minimal inflammation and non-suppurative.No or minimal anterior chamber inflammation.Can become superinfected.
Negative cultures of corneal scraping.
Vernal keratoconjunctivitis with shield ulcer
Allergic papillary conjunctivitis with a shallow, shield-shaped sterile corneal ulcer, usually located superiorly.Often bilateral.Usually occurs in children.Seasonal.No anterior chamber inflammation.
Negative cultures of corneal scraping.
Dry eye or exposure keratitis
Multiple punctate epithelial erosions that may, in severe cases, coalesce into a larger epithelial defect.Usually located inferiorly.Non-suppurative.No anterior chamber inflammation.Can become superinfected.
Negative cultures of corneal scraping.
Sterile corneal foreign body
No or minimal immune corneal infiltrate.No or minimal anterior chamber inflammation. Rust ring may be present in case of metal foreign body.Symptoms and inflammation clear after removal of foreign body.Can become superinfected.
Negative cultures of corneal scraping.
Staphylococcal hypersensitivity
Small peripheral corneal infiltrates, often multiple or bilateral, arising from an immune reaction to staphylococcal antigens.Usually associated with blepharitis.No or minimal anterior chamber inflammation.
Negative cultures of corneal scraping.
Hypoxic or toxic corneal irritation
Multiple, small, subepithelial infiltrates.Usually bilateral.Associated with poor contact lens fit, prolonged lens wear, or exposure to irritating solutions.No or minimal anterior chamber inflammation.
Negative cultures of corneal scraping.

Ki-11+ Anaplastic Large Cell Lymphoma-NHL

Hodgkin's lymphoma
Bimodal age distribution at diagnosis (peaks at mid-20s and mid-60s), pruritus, and alcohol-triggered pain. Very difficult to differentiate clinically.
Lymph node biopsy (Reed-Sternberg cells are characteristic). [29]
ALL
Acute onset, purpura, bleeding, and infection are key presenting symptoms.
Blood smear (blasts), bone marrow biopsy (blasts), flow cytometry, and immunochistochemistry (tumour cell markers), cytogenetics, PCR.
Infectious mononucleosis
A self-limiting condition that occurs in young adults (high school and university students). There is generally abrupt onset of symptoms including pharyngitis, rash, and myalgias.
Heterophile antibody test (monospot) positive, EBV titres elevated, polyclonal B-lymphocyte population on flow cytometry.
Hepatitis C (HCV)
History of IV drug use, HIV, multiple transfusions; abdominal pain, nausea, symptoms of liver disease and malaise; can be asymptomatic.
Antibody-HCV (enzyme-linked immunosorbent assay [ELISA]) or recombinant immunoblot assay, RT-PCR for HCV RNA.
Cytomegalovirus infection (CMV)
Immunocompromised host (e.g., post-transplant); cough, bone pain, visual symptoms, and diarrhoea are common presenting features.
CMV titres (elevated), CMV PCR, rectal biopsy for CMV.
Tuberculosis
Not always easy to differentiate clinically, but patient may have risk factors for tuberculosis (e.g., HIV positive, history of drug use, inadequate nutrition, inner city population), cough, malaise, and weight loss.
CXR, CT chest, purified protein derivative of tuberculin, acid-fast bacillus test, TB culture, pleural/peritoneal fluid analysis (in some cases), pleural biopsy (in some cases), bone marrow biopsy (in some cases).
HIV infection
Risk factors for sexually transmitted disease (e.g., multiple sexual partners, unprotected sexual intercourse), history of IV drug use, multiple transfusions before 1985, prior flu-like illness and rash.
ELISA (screen), Western blot (confirm), RT-PCR for HIV RNA (viral load) are diagnostic.
Syphilis infection
Consider risk factors for STD; prior genital chancre and rash.
Treponema-non-specific tests: rapid plasma reagin, Venereal Disease Research Laboratory (VDRL); Treponema-specific tests (fluorescent treponemal antibody absorption [FTA-ABS]; micro-haemagglutination Treponema pallidum [MHA-TP]) are diagnostic.
Sarcoidosis
Young or middle-aged, cough, dyspnoea, skin lesions, Bell's palsy, and malaise; may be asymptomatic.
CXR, CT chest (hilar adenopathy), bronchoscopy with biopsy of lymph nodes (non-caseating granulomas).
Rheumatoid arthritis
More common in females; joint symptoms (pain, swelling, heat, stiffness).
Rheumatoid factor (IgM antibody) elevated titre; ESR elevated; synovial fluid analysis.
Systemic lupus erythematosus (SLE)
Much more common in females; characteristic rash (may be butterfly type), photosensitivity, skin lesions, oral ulcers, myalgia, arthritis, and neurological symptoms.
ANA, anti-double-strand DNA, anti-Sm antibodies, abnormal FBC, proteinuria; American Rheumatology Association (ARA) criteria for diagnosis. [30]

Kwashiorkor

Marasmus
Malnutrition without oedema, but a weight for height/length (SD score) <-3.
Clinical diagnosis.
Undernutrition
Malnutrition without oedema and a weight between 60% and 80% of the median weight for age.
Clinical diagnosis.
Congestive heart failure
History of congenital heart disease, heart murmur; child may have hepatomegaly and hypoxaemia.
Echocardiography indicates primary anatomical heart lesion.
Glomerulonephritis
Child may have haematuria, renal failure, and decreased urine output with or without hypertension.
Proteinuria on urinalysis.Elevated urea or creatinine in serum.
Nephrotic syndrome
Nephrotic syndrome associated with marked ascites, or pleural effusions; no skin dermatosis present.
Proteinuria on urinalysis.Elevated urea or creatinine.
Hepatic cirrhosis
Chronic condition; jaundice, splenomegaly, and ascites are common; multiple angiomata of the skin often seen in cirrhosis. Child may have oesophageal varices.
Liver function tests: elevated bilirubin, serum transaminases, reduced serum albumin, and prolonged coagulation.
Haemolytic anaemia
Pallor of mucous membranes and conjunctiva. Child may have signs of cardiac failure.
MCHC; may show reticulocytes or spherocytes.Reticulocyte count; indicates appropriate marrow response to anaemia. Rise should be 4% to 5%, but may be much higher.Unconjugated bilirubin; elevated but not more than 5 g/dL unless child also has liver failure.
Allergic reaction
Oedema is usually asymmetrical and not dependent. Pruritus localised to the site of oedema; usually presents peri-orbitally.
Trial of treatment: improves with administration of an antihistamine or norepinephrine (noradrenaline) if severe reaction occurs with marked facial oedema and swelling.
Protein-losing enteropathy
Clinical presentation of PLE varies widely, reflecting its diverse aetiologies.Presence of PLE does not preclude a diagnosis of concomitant kwashiorkor.
Faecal alpha-1 antitrypsin should be tested for in high resource settings.
Lymphoedema
Usually brawny non-pitting oedema, with adenopathy.
Lymphoscintigraphy; increased tracer uptake into soft tissue and lymphatic webs, localised to affected area.

Labyrinthitis

Vestibular neuritis
Similar presentation to labyrinthitis but no hearing loss.Vertigo is exacerbated by change in head position with respect to gravity.
Normal audiogram.
Benign positional vertigo
Similar presentation to labyrinthitis but no hearing loss.
Normal audiogram.A positive Hallpike's test (rotatory nystagmus and reproduction of symptoms).
Meniere's disease
Fluctuating hearing loss, low-pitch tinnitus, low-frequency hearing loss, repeated episodes of vertigo.
Complete audiological evaluation.Includes pure-tone air and bone conduction, speech audiometry, tympanometry, and otoacoustic emissions.Typically reveals sensorineural hearing loss mainly in the low frequencies, although other configurations of hearing losses may be present.
Acoustic neuroma
Small acoustic tumours typically present as unilateral high-frequency hearing loss with difficulty hearing on the telephone on affected ear. Word discrimination score is greatly reduced when compared with pure-tone air and bone conduction testing (phonemic regression); rollover phenomenon, absent or elevated acoustic reflexes, abnormal findings on stapedial reflex decay, and abnormal auditory brainstem response.Hearing tests may be normal in patients with small acoustic neuromas.
MRI with gadolinium contrast will show a tumour involving the acoustic nerve.
Posterior fossa cerebrovascular accident
Ataxia, negative Romberg's test, dysarthria, dysphagia, hoarseness, facial paralysis, facial numbness, contralateral lower extremity weakness.
Audiogram reveals sensorineural hearing loss.CT scan of head.
Temporal bone fracture
Recent head trauma.
CT scan of head delineates extent of fracture.
Inner ear malformations
Progressive hearing loss.
MRI or CT scan of head reveals the malformation. Possible findings include atresia or malformation of ossicular chain, abnormal incus, or missing cura of the stapes.
Multiple sclerosis
Symptoms are often asymmetric and involve only one side of the body or one limb.Mild dragging of the foot and spasticity are often present.
MRI head reveals demyelinating lesions. Sagittal fluid-attenuated inversion recovery (FLAIR) images distinguish demyelinating lesions from non-specific white matter changes.
Labyrinthine haemorrhage
Similar presentation to labyrinthitis.
MRI T1-weighted images without contrast will show intra-labyrinthine hyper-intensity.
Temporal bone neoplasm
Retro-tympanic mass, facial nerve paresis, lower cranial nerve deficits.
MRI or CT scan of head will show tumour.

Lactase deficiency

Coeliac sprue
May manifest later in adult life as well as in childhood.Weight loss usually accompanies the diarrhoea.Systemic symptoms include ataxia, convulsions, bone pain, short stature, infertility.Increased risk of gastrointestinal malignancy. [32]Papulovesicular rash over the extensor surfaces of legs and arms, trunk, buttocks, and neck if dermatitis herpetiformis present. [33]
Routine laboratory biochemistry may reveal an iron and/or folic acid (rarely B12) deficiency anaemia, elevated PTH, elevated alkaline phosphatase, and hypocalcaemia.Tissue transglutaminase antibodies (TTG) are raised and antiendomysial antibodies (EMA) are positive. If coeliac serology is negative, IgA levels should be checked as 2% to 5% of patients with coeliac disease are IgA deficient. [32] TTG is more sensitive and EMA is more specific.Small bowel biopsy will show abnormalities ranging from increase in intraepithelial lymphocytes and crypt hyperplasia to villous atrophy. [34]Reduced bone mineral density is present in >70% of patients.
Sucrase-isomaltase deficiency
Autosomal recessive inherited deficiency.Symptoms are evoked by sugar, not milk. [35]Homozygotes have lifelong symptoms, while heterozygotes may have mild symptoms as infants and no symptoms as adults.Affects 10% of the Inuit of Greenland but only 0.2% of North Americans.
Stools contain non-hydrolysed sucrose; however, hydrolysation by a special technique is needed before testing for reducing substances.Diagnosis usually achieved by sucrose hydrogen breath test.In view of reports of 20% to 30% false positives, diagnosis may need to be confirmed by small-intestinal biopsy showing reduced sucrase-isomaltase.
Cows' milk protein intolerance
Reported in 2% to 5% of infants within the first 1 to 3 months of life.Typically resolves by 1 year of age. [36]May be confused with extremely rare congenital form of lactase deficiency, but diarrhoea less severe and doesn't always start on the first day of exposure to milk.
Prick test with cows' milk and cows' milk proteins, specific IgE antibodies, and challenge test with cows' milk confirms diagnosis in most patients.Tests for lactase deficiency are negative.
Giardiasis
Diarrhoea caused by a waterborne parasite, Giardia lamblia (one of the two most common gastrointestinal parasites in the US). History of water contamination may suggest diagnosis.Significant weight loss and steatorrhoea are present in 60% to 70% of patients.
No peripheral leukocytosis or eosinophilia, and white cells are usually absent in stool samples. Multiple stool specimens are needed to reveal parasite.Immunoassays for antigen detection and immunofluorescence for parasite are more accurate, and sensitivity and specificity are >90%. [37]
Irritable bowel syndrome
Typically recurrent abdominal pain or discomfort associated with a change in stool frequency or form. Pain or discomfort may be relieved by defecation.A large number of patients have coexistent (or underlying) lactose intolerance, and symptoms can worsen after ingestion of lactose. [1] [38]
There is no single diagnostic test to confirm diagnosis.Coeliac serology, including anti-TTG and anti-EMA antibodies, is negative.Lactose hydrogen breath test is negative except in cases where either underlying diagnosis is lactase deficiency or both conditions coexist.
Tropical sprue
Chronic diarrhoeal illness initiated or sustained by a still undefined infection. Patients have usually lived for more than 1 month in countries where tropical sprue exists. Most patients have steatorrhoea and progressive weight loss.Relapse rate is substantial in treated patients who remain in, or return to, areas where tropical sprue is endemic. [39]
Low vitamin B12 and folate serum levels with megaloblastic anaemia, hypoalbuminaemia, hypocalcaemia, and hypomagnesaemia are present due to malabsorption. Other causes of malabsorption should be excluded.Endoscopic and histological findings are similar to untreated coeliac disease, but negative TTG with normal serum IgA level will help with diagnosis.Treatment with tetracycline for 6 months completely reverses intestinal and haematological abnormalities in most patients. [39]
Eosinophilic enteritis
Can affect any part of the gastrointestinal tract and usually presents with anaemia and weight loss, as well as diarrhoea and abdominal pain. [40]Up to 50% of patients may be atopic, or have a history of food intolerance or allergy.
Endoscopic or laparoscopic biopsy of affected bowel shows histology with significant eosinophilic infiltrates. [40]Peripheral eosinophil count and serum IgE levels may be raised.
Autoimmune enteropathy
Rare disorder that presents in infancy with severe intractable diarrhoea and failure to thrive. It may be isolated or occur as part of IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome. [41]
Small bowel biopsies show severe villous atrophy and extensive lymphocytic infiltration.Anti-enterocyte antibodies, when present, confirm the diagnosis. [41]Coeliac serology, including TTG and EMA, is negative.
Small bowel bacterial overgrowth
History may reveal conditions that alter motility, intestinal anatomy, and gastric acid secretion (e.g., use of proton pump inhibitors, and anatomical disturbances in the bowel such as diverticula, fistulae, and blind loops created after surgery). [42]Improvement of diarrhoea after taking antibiotics for some other illness is suggestive of diagnosis.
Culture of jejunal fluid grows in excess of 10^5 bacteria/mL.A peak of breath hydrogen excretion within 2 hours from the ingestion of 50 g of glucose is consistent.A trial of treatment with antibiotics for 1 week may help in the diagnosis if symptoms show an improvement.
Microscopic colitis (lymphocytic or collagenous)
Soft to watery diarrhoea and weight loss, as well as abdominal pain. [43]Usually affects middle-aged patients, but can affect children. [43]Normal physical examination.
A small number of patients may have slight anaemia, hypokalaemia, and high ESR, but positive auto-antibodies is more common.Colonoscopy usually shows macroscopically normal colonic mucosa, though mild mucosal oedema, erythema, and friability may be seen. Colonic biopsies reveal changes typical of microscopic colitis, including either increased intra-epithelial lymphocytes (lymphocytic colitis) or sub-epithelial collagen deposition (collagenous colitis).

Lambert-Eaton myasthenic syndrome

Botulism
Subacute onset of generalised, descending weakness with diplopia, ptosis, dysarthria, dysphagia, and respiratory failure. Prominent autonomic dysfunction with dilated pupils, hypotension, bradycardia, diarrhoea followed by constipation, and urinary retention. LES is differentiated by the subacute onset and by identifying exposure to botulinum toxin.Careful clinical examination is essential.
May be distinguished from LES by post-exercise or post-tetanic facilitation that may last for minutes. Mouse bioassay to confirm botulinum toxin intoxication is available, although results may be delayed for several days.
Myasthenia gravis
Suggestive features include prominent ocular weakness that spares the pupils, and normal tendon reflexes. [32]Autonomic dysfunction is not caused by myasthenia gravis and is an important distinction between LES and myasthenia gravis.
Abnormal post-exercise or tetanic facilitation (>100%) usually differentiates LES from myasthenia gravis.The presence of acetylcholine receptor (AChR) or MuSK antibodies strongly suggests MG, although up to 13% of patients with LES have AChR antibodies, and myasthenia gravis/LES overlap syndromes do occur rarely. [29]
Myopathy
Progressive weakness without autonomic features may be seen in mitochondrial, inflammatory, andsome late-onset muscular dystrophies. Fluctuation in strength or facilitation with exercise is not noted and reflexes are preserved. FHx is frequently positive in mitochondrial and late-onset muscular dystrophies.
Elevations in serum creatine kinase suggest a myopathic process, although they may be normal. EMG differentiates a myopathic process, whereas muscle biopsy is confirmatory.
Chronic inflammatory demyelinating neuropathy
Progressive weakness with loss of tendon reflexes; autonomic symptoms may be present. Sensory examination is typically abnormal. Careful clinical examination typically differentiates LES from inflammatory neuropathy.
Nerve conduction studies confirm a peripheral neuropathic process.Absence of voltage-gated calcium-channel (VGCC) antibodies.
Guillain-Barre syndrome
Can be difficult to differentiate because of similar clinical characteristics.In GBS, patients may have a hx of influenza-like or respiratory illness or gastroenteritis before onset of neurological symptoms; no prior hx of malignancy or auto-immune disease.Classic presentation is a progressive symmetrical muscle weakness affecting lower extremities before upper extremities, and proximal muscles before distal muscles, accompanied by paraesthesias in the feet and hands.
Nerve conduction studies show a patchy demyelination, slowing of motor nerve conduction velocities, prolonged distal and F-wave latencies, and dispersed response.Absence of VGCC antibodies.Presence of subtype-specific antiganglioside antibodies.

Langerhans cell histiocytosis

Seborrhoeic dermatitis
No differentiating signs and symptoms from Langerhans cell histiocytosis (LCH) with skin involvement, especially in newborns.
Tissue biopsy: negative for CD1a and langerin (CD207).
Juvenile xanthogranuloma (JXG)
Can mimic LCH very closely in a number of tissue sites (especially the skin), and sometimes can be multi-systemic.Dermal JXG can be seen in children after LCH. [59]
Tissue biopsy: negative for CD1a and S100; positive for factor XIIIa, fascin, CD68, CD163, and CD14.
Rosai-Dorfman disease (RDD)
Also called sinus histiocytosis with massive lymphadenopathy.Most patients present with bilateral painless cervical lymphadenopathy with fever, night sweats, and weight loss.Extranodal disease occurs in 40% of patients, with skin, lung, liver, CNS, and bone being most commonly involved. [60]Bone RDD may mimic the lesions of healing and involuting LCH. Coexistence of LCH and RDD has been reported. [61]
White blood cell count: leukocytosis.Serum electrophoresis: hypergammaglobulinaemia.Tissue biopsy: positive for S100, fascin, CD68, and CD163; intracytoplasmic emperipolesis of lymphocytes, neutrophils, and plasma cells is common.
Osteomyelitis
Difficult to distinguish clinically from LCH with bone involvement.Chronic multifocal osteomyelitis can be confused with multifocal bone disease and may have few or no constitutional symptoms.
Tissue biopsy: negative for CD1a and langerin (CD207).Cultures from biopsy sample: positive for bacteria or atypical mycobacteria.
Ewing's sarcoma
Difficult to distinguish clinically from LCH with bone involvement.
Tissue biopsy: negative for CD1a and langerin (CD207).X-ray: aggressive radiological features such as significant periosteal reaction, poorly defined borders, and onion-skinning are typical. With healing LCH lesions, there is re-calcification and development of a well-defined sclerotic rim.
Osteosarcoma
Difficult to distinguish clinically from LCH with bone involvement.
Tissue biopsy: negative for CD1a and langerin (CD207).X-ray: with healing LCH lesions, there is re-calcification and development of a well-defined sclerotic rim.
Tuberculosis
Disseminated tuberculosis may mimic multi-system disease.Progressive fever and weight loss are usually present.
Sputum smear: positive for acid-fast bacilli.Sputum culture: positive.Tuberculin skin testing: millimetres of induration.Chest x-ray: normal; abnormal typical for TB; abnormal atypical for TB.Tissue biopsy: caseating granulomas typically seen.
Acute lymphoblastic leukemia (ALL)
Can be confused with multi-system disease in the presence of hepatosplenomegaly, lymphadenopathy, fever, pallor, and petechial rash.
Bone marrow aspirate and biopsy: bone marrow hypercellularity and infiltration by lymphoblasts.Peripheral blood smear: leukemic lymphoblasts with or without hyperleukocytosis.Serum electrolytes: hyperuricaemia, hyperkalaemia, hyperphosphataemia.
Acute myelogenous leukemia (AML)
Neonatal acute monoblastic leukemia can present with skin rash that can mimic LCH with skin involvement.
Bone marrow aspirate and biopsy: bone marrow hypercellularity and infiltration by myeloblasts.Peripheral blood smear: myeloblasts, hyperleukocytosis, or pancytopenia.
Non-Hodgkin's lymphoma (NHL)
Can be difficult to differentiate from LCH in the presence of lymphadenopathy and systemic symptoms.
Tissue biopsy: negative for CD1a and langerin (CD207) and positive for T- or B-cell markers.
Pituitary adenoma
Can also cause central diabetes insipidus.No history of skin rash, bone pain, or recurrent otitis.
CT/MRI pituitary with contrast: sellar mass.
Craniopharyngioma
Can also cause central diabetes insipidus.No history of skin rash, bone pain, or recurrent otitis.Macrocephaly and hydrocephalus.
MRI brain with contrast: variable; T1 signal (T1 hyperintensity secondary to high protein content in cystic component); mixed solid and cystic components with enhancement of the solid component and cyst wall; T2 and fluid attenuation inversion recovery (FLAIR) show heterogeneous signal in the solid components and cyst hyper-intensity; calcification has low signal on T2.Biopsy and histology: adamantinous/squamous epithelial tumour; calcification.

Large bowel obstruction

Acute colonic pseudo-obstruction
Impressive abdominal distension yet little or no abdominal tenderness.Around 49% of patients have underlying surgical disorder, 45% have precipitating medical disorder, and 6% of cases are idiopathic. [20]Typically seen in older patients who are admitted to hospital with a severe illness, for example, chest infection, myocardial infarction, cerebrovascular accident, renal failure, retroperitoneal malignancy, orthopaedic trauma, or electrolyte disturbances.Drug history may include neuroleptics, opioids, and laxatives.Concomitant conditions may include diabetes, myxoedema, scleroderma, Parkinson's disease, lupus, hyperparathyroidism, and recent metabolic illness.Recent trauma or orthopaedic surgery.
Gas in the rectum in the absence of a rectal examination is often present, and this has been demonstrated radiographically in right lateral decubitus and prone lateral views. [21]Contrast enema confirms diagnosis and excludes mechanical causes in almost all cases.
Chronic/idiopathic megacolon
Long-standing history of constipation, diarrhoea, or incontinence.Visceral neuropathy. May also be part of an acquired visceral neuropathy (e.g., Chagas' disease).Drug history may include risperidone.Preceding viral infection.Recurrence after resection implies a misdiagnosed megacolon.
Difficult to differentiate; can be radiologically similar to sigmoid volvulus and respond rapidly to rectal tube decompression.Colonic transit studies and anorectal manometry assist in this difficult diagnosis. A slow colonic transit may be identified. Anorectal physiology excludes Hirschprung's disease where a normal recto-anal inhibitory reflex is identified.
Toxic megacolon
Presence of an initial colitis of any cause.Signs of sepsis (e.g., fever, tachycardia, hypotension, poor capillary refill) in early stages.
Diagnosis may be apparent from clinical picture.Plain abdominal x-ray may show 'thumb printing' or intraluminal soft tissue mass (pseudopolyps).Cautious colonoscopy confirms the diagnosis not only by the typical mucosal appearance, but also by biopsy.Colonoscopy should be with minimal insufflation and rarely proceeds beyond the rectum and sigmoid once colitis is confirmed endoscopically, owing to the risk of perforation.
Endometriosis
Previous history of endometriosis.History of pelvic pain.Colonic endometriosis causing obstruction is rare.Endometriosis has been termed the 'great mimicker'.
Ultrasonography (transabdominal and transvaginal) shows endometriotic cysts, but has a limited role in detecting endometrial implants.CT scan may identify cystic masses, but the features are frequently non-specific for diagnosing endometriosis.
Pseudomembranous colitis
Recent history of antibiotic or immunosuppressant use.Profuse, foul-smelling diarrhoea.
Elevated WBC count.Colonoscopy may identify pseudomembranes and exclude mechanical obstruction.Stool culture isolates Clostridium difficile.

Laryngeal cancer

Laryngitis
Symptoms <7 days, preceded by URI, and ordinarily self-limiting. May present with airway distress and high fever. Exudative tonsillopharyngitis with fever and anterior cervical lymphadenitis is highly suggestive of a bacterial origin.
Generally a clinical diagnosis, although indirect laryngoscopy may be performed to rule out laryngeal cancer. Chronic laryngitis lasting >3 weeks should be referred to a specialist.
Fungal laryngitis
There is often an associated infection of the oral cavity and oropharynx demonstrating signs of thrush.More common in patients who have hx of immunosuppression or who take corticosteroids (in particular inhaled corticosteroids).Neck masses are uncommon.
Biopsy and fungal culture distinguish this disorder from malignancy.
Sarcoidosis
Often associated with nasal congestion and obstruction, and dyspnoea on exertion. Patients may have a known diagnosis of sarcoidosis.
Localised pale oedema, submucosal nodules on laryngoscopy, non-caseating granulomas on histopathology.
Tuberculosis
Hx of known TB, PPD positive, known risk factors for TB infection (e.g., homelessness, incarceration, HIV positive).
Laryngoscopy shows multiple nodular lesions (similar findings to laryngeal cancer). Biopsy and culture of lesions distinguish TB. [35]
Wegener's granulomatosis
Patients may present with nasal congestion, nasal crusting, cough and difficulty breathing, and haematuria. May have a known hx of Wegener's granulomatosis.
Laryngoscopy shows acute, erythematous friable mucosa and subglottic narrowing. [36] Biopsy of lesions is diagnostic; may demonstrate vasculitis. Serum tests of cytoplasmic-staining antineutrophil cytoplasmic antibodies may be diagnostic, but sensitivity is only 65% to 75%.

Laryngitis

Tonsillitis
There may be no significant difference in signs and symptoms, but hoarseness is more pronounced in laryngitis.
Indirect laryngoscopy will not show erythema and oedema of the laryngeal structures in acute tonsillitis.
Infectious mononucleosis
Hepatomegaly and splenomegaly usually present.Rash and generalised fatigue may occur.Exudates are creamy in colour and usually do not extend beyond the tonsils.There is no bleeding when the exudates are removed.
Positive heterophile antibody test or positive serology test.
Reflux laryngitis
No sign or symptom of an acute infection.
Indirect laryngoscopy shows no exudative changes in the larynx.There may be hyperaemia of the arytenoids and generally of the posterior true vocal folds, but not diffusely of the entire endolarynx.There may be improvement in symptoms with a trial of proton pump inhibitor therapy.
Allergic rhinitis
No sign or symptom of an acute infection.Other allergy-related hx or symptoms (e.g., sneezing, nasal pruritus, allergic conjunctivitis) are present.
Improvement with a therapeutic trial of antihistamines or intranasal corticosteroid medication.Allergy skin prick testing or in vitro-specific IgE determination may detect allergic response to a specific allergen.
Laryngeal carcinoma
There may be no difference in signs and symptoms between laryngeal cancer and tuberculous laryngitis.
A direct laryngoscopy should be performed and biopsies obtained.Biopsy will demonstrate malignancy in patients with laryngeal carcinoma, whereas biopsy may show granulomatous necrosis and acid-fast bacilli in patients with TB infection.

Laryngomalacia

Vocal cord palsy
Clinical presentation may be similar, although this is often present from birth. Patients have significant feeding problems (choking episodes and recurrent aspiration) and an abnormal or absent cry.Patients may have a hx of birth trauma, Arnold-Chiari malformation, hydrocephalus, or potential for iatrogenic injury, such as recent cardiac surgery.
Flexible laryngoscopy demonstrates immobility of 1 or both vocal cords.
Subglottic stenosis
Clinical presentation may be similar, although stridor may be biphasic rather than inspiratory. Feeding difficulties are usually less severe than in laryngomalacia.Patients may have hx of previous intubation if stenosis is acquired.
Lateral neck radiograph or CXR may demonstrate subglottic narrowing.Flexible laryngoscopy is usually inadequate for diagnosis.Rigid laryngobronchoscopy reveals stenosis and allows formal sizing (based on endotracheal tube sizes). [26] View image
Laryngeal web
Clinical presentation may be similar, although patients have an abnormal, often high pitched cry.May be associated with velocardiofacial (Shprintzen's) syndrome.
Endoscopic examination of the larynx demonstrates the anterior glottic web. View image
Laryngeal cleft
Clinical presentation may be similar, although significant feeding problems (choking episodes and recurrent aspiration) may occur.
Endoscopic examination of the larynx demonstrates the defect in the posterior glottis, extending from the interarytenoid region for a variable distance through the cricoid into the tracheoesophageal septum. View image
Subglottic haemangioma
Clinical presentation may be similar; 50% of children with a subglottic haemangioma have a concurrent cutaneous lesion.
Rigid bronchoscopy allows direct visualisation of the vascular lesion. These lesions typically involve the posterolateral aspect of the subglottis; may be unilateral, bilateral, or circumferential.
Laryngeal or vallecular cyst
Clinical presentation may be similar but typically is present from birth.May be exacerbated by supine posture and in the case of vallecular cysts, may be improved with chin lift/jaw thrust. With vallecular cysts, the cry is usually unaffected but may be abnormal with laryngeal cysts.Large vallecular cysts may sometimes be seen with direct examination of the oropharynx.
A lateral x-ray may show a soft tissue density suggesting the presence of a cyst.Endoscopic examination of the larynx reveals these cysts. View image

Lead toxicity

Iron deficiency anaemia
Anaemia is rare with lead poisoning, except for high-level exposure. Iron deficiency is usually related to dietary deficiency or blood loss. Responds to iron supplementation with correction of anaemia.
Iron store measured by serum iron, iron-binding capacity, transferrin, ferritin, or bone marrow indicates iron deficiency.
Non-lead peripheral neuropathy
No hx of lead exposure.Faster rates of symptom progression.
Low blood lead level.Blood/urine testing may reveal other toxicants.Appropriate cultures and serology reveal infectious causes.Positive immune markers for chronic inflammatory and immune diseases.Characteristic nerve conduction study/EMG findings for neurological syndromes.
Arsenic poisoning
May have neuropathy with skin lesions, including keratoses.May have hx of exposure to arsenic.
Hair arsenic.24-hour urine collection for arsenic during chelation therapy.
Encephalitis
No hx of lead exposure.May have hx of exposure to NSAIDs, antibiotics, antivirals, immunomodulators, or anticonvulsants.Lead encephalopathy often has prominent cerebellar signs, depressed sensorium, and seizures.
Low blood lead level.Detection of Plasmodium in peripheral blood smear or detection of bacterial and viral infections in blood, throat, and sputum cultures.CT/MRI scanning reveals characteristic findings of the underlying cause.Analysis and culture of CSF reveals characteristic findings, infections, and infection- or paraneoplastic-related antibodies.

Legg-Calvé-Perthes' disease

Septic arthritis
Acute onset.Systemic symptoms.Unilateral involvement.Acute pain in the hip.Marked restriction in movement.
Elevated WBC count.Positive blood cultures.X-ray shows widened joint space.Joint effusion on ultrasound examination.Joint aspiration may confirm the infection.
Transient synovitis of the hip
Acute onset.Prior history of viral illness.Mild systemic features.Unilateral involvement.Restricted motion with minimal pain.Spontaneous improvement over 24 to 48 hours.
Normal WBC count.Negative blood cultures.Normal x-rays.Ultrasound examination shows joint effusion.Joint aspiration is sterile.
Sickle cell disease
Acute abdominal pain.Systemic symptoms.Unilateral involvement with associated long bone osteomyelitis.
Sickling test positive.
Juvenile idiopathic arthritis
Acute or chronic presentation.Single or multiple joint involvement.Systemic symptoms.Effusion of the affected joints.Recurrence of acute episodes.
High WBC count in acute phase.Rheumatoid factor positive.Joint aspirate shows white cells, no crystals or organisms.X-rays may show decreased joint space.

Legionella infection

Bacterial pneumonia
No differentiating features in history and physical examination.
Tests for Legionella are negative. Culture of sputum, blood, or pleural fluid may grow other organisms that cause bacterial pneumonia.
Hospital-acquired pneumonia
No differentiating features in history and physical examination.
Tests for Legionella are negative. Other bacterial organisms may be cultured.
Community-acquired pneumonia
No differentiating features in history and physical exam.
Tests for Legionella are negative. Other bacterial organisms may be cultured.
Influenza
No differentiating features in history and physical examination.
Tests for Legionella are negative. Viral serology or culture may be positive for influenza.

Leishmaniasis

hyper-reactive malarial splenomegaly (HMS)
Formerly called tropical splenomegaly syndrome.The clinical presentation can mimic visceral leishmaniasis but fever is a less consistent feature. [62] A clinical response to antimalarials also helps distinguish the diagnoses.
Major criteria for HMS diagnosis are splenomegaly greater than 10 cm on CT scan, high titres of antimalarial antibodies and IgM titres greater than 2 standard deviations above the mean of the local population.Plasmodium species in the peripheral blood smear is typically negative.The presence of high IgM titres helps in differentiating the disease from visceral leishmaniasis.In practice, visceral leishmaniasis must be ruled out by specific serological or parasitological tests. [62]HMS remains an exclusion diagnosis in remote endemic areas where IgM and antimalarial antibody titres cannot be measured.
malaria infection
As the disease is more acute than visceral leishmaniasis, patients present with fever of shorter duration and mild or absent splenomegaly.Recurrent malaria can be more difficult to distinguish from visceral leishmaniasis, as fever can be longer lasting and intermittent, and the spleen markedly enlarged. [63]Unresponsive patients to effective antimalarials should be investigated for visceral leishmaniasis, as dual infection is common in endemic areas.
Malaria can be diagnosed by microscopic examination of a stained thin and thick smear of peripheral blood or by a rapid diagnostic test detecting circulating antigens specific to P falciparum or other species. [63]
schistosomiasis
Splenomegaly, secondary to portal HTN, can be massive.Chronic schistosomiasis does not cause fever but patient may present with concomitant infection such as malaria, typhoid fever or TB. [64]
Chronic Schistosoma mansoni infection is diagnosed by the presence of characteristic eggs in the stools or by antibody-based assays.Abdominal ultrasound, CT scan or MRI show the typical features of hepatic schistosomiasis and the signs of portal HTN. [64]

Leprosy

Psoriasis
Presents with widespread scaly patches of the skin, especially on the extensor aspects of joints. May be involvement of the nails and arthritis.Patient has familial predisposition; condition may be aggravated by stress.There is no neural involvement, and skin nodules are not found.When skin plaques are scraped, pinpoint bleeding may be seen from the skin below (Auspitz's sign).
Diagnosis is usually based on the appearance of the skin. There are no special blood tests or diagnostic procedures but a skin biopsy, or scraping, may be needed to rule out other disorders and to confirm the diagnosis.Skin biopsy histology shows regenerative changes of the epithelium, absence of granulomas, and clubbed rete pegs if positive for psoriasis. No acid-fast-bacilli (AFB) are present on special stains.
Eczema
Features widespread dryness of the skin and recurring skin rashes with redness, skin oedema, itching, crusting, flaking, blistering, cracking, oozing, or bleeding.Areas of temporary skin discoloration may appear and are sometimes due to healed lesions, although scarring is rare.Likely to be found on the flexor aspect of joints. May be a history of allergy. There is no neural involvement, and skin nodules are not found.
Skin biopsy and histopathology show non-specific inflammation in acute, chronic, and healing phases of eczema, but granulomas are uncommon.Skin testing (patch testing) may be diagnostic in allergic eczema, and FBC may show peripheral eosinophilia. No acid-fast bacilli (AFB) are present on special stains of skin scrapings or skin biopsy.
Lichen planus
Presents with skin and oral lesions and, rarely, with oesophageal symptoms. Skin may show macules, papules, and rash. There is no neural involvement, and skin nodules are not found.
Skin biopsy and histopathology show hyperparakeratosis with thickening of the granular cell layer, a saw-tooth appearance of the rete pegs, degeneration of the basal cell layer, and infiltration of inflammatory cells into the sub-epithelial layer of connective tissue. No acid-fast bacilli (AFB) are present on special stains.
Scars
Burns and other injuries may leave behind anaesthetic scars. There is a history of trauma or burn. There is no neural involvement, and skin nodules are not found.
Skin biopsy and histopathology show an increase in collagen within the dermis without inflammation or granuloma formation. No acid-fast bacilli (AFB) are present on special stains.
Blastomycosis
Blastomyces dermatitidis is endemic to North America and is a fungal organism present in soil. There may be a history of contact with infected dogs or cats.Presents with systemic symptoms of fever and with pneumonia. Skin lesions are widespread and ulcerated with typical pustules around the margin. There is no neural involvement, and skin nodules are not found.
Characteristic broad-based, budding fungal organisms in sputum or tissues by cytology or histology. Tissue biopsy of skin or other organs is negative for acid-fast bacilli (AFB).
Syphilis
Syphilitic skin lesions may often closely resemble the maculae of leprosy, but the absence of sensory changes and reaction to treatment are sufficiently distinctive.
The infectious organism is Treponema pallidum. Skin biopsy and histopathology may show inflammatory changes, depending on the stage at presentation. Secondary syphilis may be associated with granuloma formation, but no acid-fast bacilli (AFB) are present on special stains.The venereal disease research lab (VDRL) reaction alone cannot always be depended on in differential diagnosis, as false-positive reactions are not uncommon in lepromatous leprosy, in which case polymerase chain reaction (PCR) test may be more sensitive and specific.Examination of skin scrapings or skin biopsy with dark-field microscopy may visualise the spirochetes.
Yaws
Skin lesions may often closely resemble the maculae of leprosy, but the absence of sensory changes and reaction to treatment are sufficiently distinctive.Largest group afflicted is children aged 6 to 10 years. Lesions are most commonly on the head, hands, and feet, with a history of previous cuts or abrasion.
The infectious organism is Treponema pertenue. Disease is identified from positive serology. Examination of skin scrapings or a skin biopsy with dark-field microscopy may visualise the spirochetes.
Mycosis fungoides
Early lesions might be mistaken for early nodular leprosy. Presents rarely earlier than 20 years of age and is most common after 50 years. Late-stage disease may have systemic involvement.
Skin involvement by cutaneous T-cell non-Hodgkin's lymphoma. Biopsy and histopathology are diagnostic, with infiltrates of neoplastic CD4 T cells that show clonality on T-cell gene re-arrangement studies.
Leukoderma (white patches or vitiligo)
Frequently associated with leprosy, but depigmentation in leukoderma is more complete and sensory changes are absent. May be associated with stress.
Skin biopsy and histopathology of depigmented skin lesions shows loss of melanocytes and loss of melanin from the epidermis. No granulomas or acid-fast bacilli (AFB) are present.
Lupus vulgaris
Highly likely to be mistaken for leprosy lesions, and in both diseases acid-fast bacilli are difficult to demonstrate. Lupus produces painful, ulcerating skin lesions around the mouth, eyes, nose, and ears. There is a greater tendency to scar formation, and there are no sensory changes.
Skin biopsy will show granulomatous inflammation with Mycobacterium tuberculosis acid-fast bacilli (AFB) on special stains. Distinction from leprosy is difficult, but in cutaneous tuberculosis there is often a proliferation reaction of the epidermis, areas of ulceration, absence of nerve destruction, marked increase in the reticulin, significant fibrosis, and, occasionally, caseous necrosis.
Cutaneous leishmaniasis
Cutaneous leishmaniasis, and in South America, espundia, may be mistaken for leprosy. Lesions on the skin of the face tend to concentrate around the mouth and nose and form a more raised margin than those in leprosy.
Skin scraping, skin biopsy, and histopathology. Demonstration of the Leishman-Donovan body will always settle the matter but leishmanial, lupus-like lesions on the ears may cause difficulty.

Leptospirosis

Hantavirus
Severe respiratory symptoms leading to adult respiratory-distress syndrome.Symptoms do not present in a biphasic form.Exposure to specific endemic areas favours Hantavirus.
Diagnosis confirmed by PCR test from blood or tissue specimens or immuno-histochemical testing.
Influenza
Differs in epidemiology; influenza peaks in the winter and troughs in the summer.Shorter incubation period (1 to 2 days).Renal and hepatic failure and haemorrhagic diathesis are not seen in influenza.Symptoms do not present in 2 phases.
Positive influenza A and B antigen test and/or positive viral culture.
Dengue fever
Presenting signs and symptoms similar to leptospirosis, except conjunctival suffusion, which is not present in dengue fever.Dengue fever does not present in 2 phases.
Positive serological test will confirm diagnosis and differentiate among aetiologic agents. [36]
Haemorrhagic fever
Similar presentation in both haemorrhagic fever and leptospirosis.Haemorrhagic fever will occur after exposure to particular endemic areas, whereas leptospirosis is endemic worldwide.
Positive leptospiral testing confirms leptospirosis and will differentiate it from haemorrhagic fever. Diagnosis is confirmed by multiple PCR assays, serological tests, and viral isolation.
Malaria
Similar presentation involving recent travel, fever, potential renal failure, and haemorrhagic complications.
Malaria diagnosis is confirmed with peripheral smear. Leptospirosis testing will be negative.
Viral hepatitis
Mainly involved in differential diagnosis for travelers. Patients usually present with fevers, jaundice, and elevated liver aminotransferases. Potentially, patients can develop acute hepatic failure.
Positive acute hepatitis serologies.

Lesch-Nyhan disease

Cerebral palsy
Owing to the occurrence of hypotonia and developmental delay early in the course of the disease, many patients are diagnosed as having cerebral palsy until the tell-tale features of LND, such as self-injury or overproduction of uric acid, are recognised.
Hyperuricaemia is not typical in cerebral palsy.Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene analysis and HPRT enzyme activity will provide definite diagnosis in cases of LND.
Diseases with developmental delay
The differential diagnosis for developmental delay is extensive. [27]LND should be suspected if delayed development is accompanied by self-injurious behaviour or evidence of excessive production of uric acid.
Hyperuricaemia is not typical in these conditions.Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene analysis and HPRT enzyme activity will provide definite diagnosis in cases of LND.
Diseases with dystonia at young age
The differential diagnosis for dystonia at young age is extensive. [28]LND should be suspected if dystonia is accompanied by self-injurious behaviour or evidence of excessive production of uric acid.
Hyperuricaemia is not typical in these conditions.Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene analysis and HPRT enzyme activity will provide definite diagnosis in cases of LND.
Other diseases with self-injury (e.g., mental retardation, autism, Prader-Willis syndrome, fragile X syndrome)
Self-injury in LND is usually more severe than in other conditions, and the prominent topographical preference for fingers is not frequently seen in other conditions. View imageSelf-injurious behaviour in LND is always accompanied by profound motor impairment. LND should be suspected when self-injurious behaviour is associated with the typical motor dysfunction emerging early in life, especially if there is also hyperuricaemia.
Hyperuricaemia is not typical in these conditions.Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene analysis and HPRT enzyme activity will provide definite diagnosis in cases of LND.

Lesser Risk B-Lineage ALL

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Lewy body dementia

Alzheimer's disease
Characterised by memory loss, reduced social and occupational functioning, diminished executive function, speech/motor deficits, personality change, and behavioural/psychological disturbance.Minimal fluctuations in level of consciousness.Cognitive exam shows short-term memory loss. Absence of significant extrapyramidal signs early in the disease.Rapid eye movement (REM) sleep behaviour disorder is not typically present.
Clinical history and examination are the best way to differentiate Alzheimer's disease from DLB.Neuropsychological testing may be helpful if there is a prominent amnestic syndrome early in the disease.Structural and functional imaging may also be of benefit.In Alzheimer's disease, there is decreased perfusion in temporoparietal regions with single-photon emission CT (SPECT)/positron emission tomography (PET).
Parkinson's disease
Considerable overlap with DLB.Visual hallucinations, paranoia, and autonomic dysfunction are common features.Motor symptoms include rigidity, resting tremor, bradykinesia, and postural instability.
MRI usually reveals global brain atrophy in these patients.
Frontotemporal dementia
Impulsive, socially inappropriate, and emotionally labile behaviour.Personality change and behavioural disturbance occur early and are prominent features.Verbal and language skills are blunted.Apathy and self-neglect are common.Onset often in 50s, progressing more rapidly than DLB.
CT or brain MRI reveals structural atrophy in the frontal lobes.PET or SPECT scanning shows reduced brain activity in the frontal and temporal lobes.Brain histology may reveal diagnostic findings (such as Pick bodies).
Vascular dementia
Deficits include memory loss, emotional lability, and focal neurological deficits consistent with stroke location.Cardiovascular risk factors may be present.Further cognitive and functional decline occurs in a stepwise manner.Subcortical depression and apathy are common.
CT or MRI scanning demonstrates areas of past infarction and perivascular ischaemia.

Lichen planus

Lichen simplex chronicus
Lichenified or thickened papules and plaques arising as a consequence of chronic rubbing.
Standard histology shows compact orthokeratosis, psoriasiform acanthosis of the epidermis, vertically oriented dermal blood vessels and collagen in the papillary dermis. [46]
Psoriasis
Anatomic distribution favouring extensor surfaces of extremities; silver scale overlying plaques; reports of pinpoint bleeding within plaques.
Standard histology shows regular acanthosis, loss of the granular layer, thinning of the supra-papillary plates, dilation of blood vessels in the superficial papillary dermis, neutrophilic abscesses in the stratum corneum and/or parakeratosis. [46]
Lichen planus pemphigoides
Tense bullae on normal skin or skin affected by lichen planus.
Standard histology shows cell-poor sub-epidermal bullae, often with lichenoid infiltrates at the bulla edges; eosinophils and neutrophils are also occasionally present. [46]Direct immunofluorescence shows linear IgG and C3 at the basement membrane zone with lichen planus pemphigoides.Indirect immunofluorescence using salt-split skin substrate causes immunofluorescence to localise at the roof of blisters. [46]
Secondary syphilis
Preceding chancre and involvement of the palms and soles; nail changes are less common.
Serological studies are positive for syphilis.Biopsies reveal superficial and deep inflammatory infiltrates containing plasma cells and T-lymphocytes. [46]
Granuloma annulare
May resemble annular lichen planus clinically but there is an absence of epidermal changes such as scale and Wickham's striae.
Standard histology shows the presence of palisading granulomas surrounding necrobiosis with mucin. [46]
Lichen sclerosus
Causes inflammation, erosion, ulceration and scarring of the genital mucosa. More responsive to treatments than genital LP.
Standard histology shows lichenoid lymphocytic infiltrates below homogenised collagen and oedema in the superficial dermis. [46] Epidermal atrophy and perivascular lymphocytic infiltrates in the mid-dermis may be observed, dependent on the age of the lesions.
Lichenoid drug eruption
Medicine histories reveal use of NSAIDs, ACE inhibitors, antimalarials and penicillamine. [42]
Standard histology demonstrates hyper-parakeratosis and eosinophils in the superficial papillary dermis. [46] [42]
Lichenoid keratosis
Single lesion manifestations.
Standard histology shows findings of lichen planus but from a single lesion.

Lichen simplex chronicus

Hypertrophic lichen planus
Localised to the shins and may be surrounded by smaller, more typical lesions of lichen planus with a polygonal border and overlying Wickham striae.
Skin biopsy demonstrates acanthosis and, often, irregular psoriasiform epidermal hyperplasia similar to LSC, but with additional band-like lymphocytic infiltrates and evidence of vacuolar change.
Hypertrophic actinic keratoses
Lesions are typically smaller than those of LSC, located on sun-exposed areas of skin, more erythematous, and associated with greater overlying hyperkeratosis. They can be painful and are rarely associated with pruritus unless in the presence of secondary LSC.
Skin biopsy demonstrates non-full thickness keratinocyte atypia, but lesions on the dorsum of the hand may show histological features of associated secondary LSC.
Squamous cell carcinoma of the skin
Lesions are located on sun-exposed areas of skin, are more erythematous, often have thick overlying hyperkeratosis, and may be painful but not pruritic.
Skin biopsy demonstrates keratinocyte atypia with evidence of dermal invasion.
Psoriasis
Symmetrical eruption not associated with the intense pruritus of LSC. Lesions are more erythematous with silvery scales and no evidence of lichenification.
Skin biopsy demonstrates regular psoriasiform epidermal hyperplasia, with confluent overlying parakeratosis and loss of the granular cell layer.
Warts
Can occur at any body site but are most commonly located on the palms and soles. Lesions are characterised by a verrucous surface with black dots and interruption of skin lines and are not associated with the intense pruritus of LSC.
Skin biopsy demonstrates verrucous epidermal hyperplasia with in-toeing of the rete ridges, tiers or parakeratosis, and occasional koilocytic change.
Scabies
Often a diffuse eruption with a dermatitic appearance. No burrows or scabetic nodules present on the genitalia.
Skin biopsy demonstrates an intense inflammatory infiltrate extending into the deep dermis and associated with increased numbers of eosinophils.Skin scrapings reveal intact mites, eggs, or scybala.
Pemphigoid nodularis (bullous pemphigoid resembling prurigo nodularis)
Diffuse blisters and urticarial lesions.
Skin biopsy demonstrates subepidermal blistering with increased eosinophils.Direct immunofluorescence studies demonstrate band-like deposition of IgG and C3 along the dermal-epidermal junction.
Mycosis fungoides
Lesions are localised to areas of the body covered by a bathing suit and are more atrophic in appearance than those of LSC.
Skin biopsy demonstrates a band-like infiltrate of T lymphocytes along the dermal-epidermal junction with scant epidermal spongiosis and epidermotropism.PCR, of a skin biopsy specimen, for T-cell gene rearrangement demonstrates a monoclonal T-cell population, which is diagnostic for the condition.

Lipoma

Liposarcoma
The majority of liposarcomas present at a size >5 cm, while most lipomas are <5 cm in size.Often feel firmer to palpation than the soft, doughy feel of a lipoma.Liposarcomas can gain a very large size, either growing slowly over many years or rapidly over a short period of time. Lipomas are generally <5cm in size and grow slowly or remain static in size.Retroperitoneal position would suggest a liposarcoma, since lipomas in this position are exceedingly rare.
Imaging with MRI or CT may provide evidence that a lesion is a liposarcoma.Histological examination of biopsy sample: adipocytes with nuclear atypia to include hyperchromasia, size variation, and nuclear membrane irregularities. Lipoblasts (atypical adipocytes with cytoplasmic vacuoles which indent the nucleus), when present in the appropriate histologic background, are strongly indicative of liposarcoma.Liposarcomas are histologically subclassified into well-differentiated, dedifferentiated, myxoid, pleomorphic and mixed types, each with a unique morphologic pattern.
Epidermoid cyst
Subcutaneous epidermoid cysts are usually rounded and firm, whereas lipomas have a characteristic soft, doughy texture.Central punctum often visible, through which a white exudate can be expressed.
Definitive diagnosis is made upon excision and histological examination.Histologic examination: benign simple cysts lined by stratified squamous epithelium with an intact granular cell layer. Within the cyst lumen, there is characteristic laminated keratin debris. In cysts that have previously ruptured, a foreign-body giant cell reaction is often present.
Abscess
Surrounded by erythema; may develop rapidly over a few days; usually warm and tender to touch.Patient may be pyrexial.
Aspiration usually yields pus.

Listeriosis

Other bacterial meningitides
There is no sign or symptom that securely differentiates listeriosis from other causes of CNS infection.Nuchal rigidity is more common in meningitis due to pathogens other than Listeria. [1] [6]
CSF Gram stain, CSF culture and blood culture are the tests of choice.Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae are common causes of community-acquired bacterial meningitis.
Other brain abscesses
There is no sign or symptom that securely differentiates listeriosis from other causes of CNS infection.
Culture and Gram stain will typically differentiate other organisms. Additionally, blood cultures are frequently positive in listeriosis.
Viral gastroenteritis
Viral gastroenteritis may be accompanied by upper respiratory symptoms.A history of consumption of foods suspicious for listeriosis may be absent.
Stool tests are negative for Listeria.
Other bacterial gastroenteritides
Social history, food-consumption history, travel history, incubation period, history of alimentary tract contamination, presence of dysentery, sporadic or epidemic cases are used to differentiate the causes clinically. Presenting signs and symptoms may be similar to listeriosis. In Shigella infection, stool may contain blood or pus.
Stool tests or serologies may be positive for organisms such as Campylobacter jejuni, Salmonella, or Shigella.
Toxoplasmosis
History of consumption of raw meat or having a house cat.Unexplained fever and generalised lymphadenitis.
Serology for IgM and IgG antibodies against Toxoplasma gondii may be present.Microscopy of an infected lymph node may confirm toxoplasmosis.
Sarcoidosis
May affect any organ, but erythema nodosum is a more specific presentation for sarcoidosis.
Chest radiography may show bilateral enlargement of hilar lymph nodes.Biopsy of lymph node or affected tissue may show granulomas without central necrosis.Hypercalciuria may be present.
Vasculitis
Systemic symptoms or signs may be similar, rendering diagnosis difficult.
Biopsy of affected organ may show thrombosis and inflammation of any size of vasculature and invasion of vessel wall by inflammatory cells.
Septic abortion
There are no distinguishing features compared to other causes.Fever and rigors in pregnant women and bacteraemia due to any site of infection may cause chorioamnionitis, fetal sepsis, and death.
Blood, placenta, amniotic fluid cultures will determine the underlying aetiological organism.

Liver abscess

Ascending cholangitis
No differentiating symptoms or signs.
Ultrasonography shows bile duct dilation and/or stones.ERCP or MRCP shows obstructing biliary stones or bile duct dilation.
Simple liver cysts
No constitutional symptoms or abdominal pain.
Ultrasonography shows unilocular fluid-filled lesion.Abdominal CT scan: simple cysts are well-circumscribed lesions that do not enhance with contrast. The lesions have attenuation consistent with water.
Echinococcal cyst
Patients are typically asymptomatic. Symptoms may occur as the cyst enlarges or ruptures.More likely in areas where species of Echinococcus have the highest prevalence (e.g., Mediterranean countries, South America, the Middle East, North Africa, some sub-Saharan African countries, China, and the Russian Federation).
Ultrasonography and abdominal CT have high sensitivity and specificity for hydatid cysts. Cysts are most commonly located in the liver and can become superinfected. [17]Typical radiographic appearance is of a calcified ring-like cyst, with septations within the cyst, and sometimes with daughter cysts present.View imageEIA can also be used for the diagnosis of hepatic echinococcosis.Aspiration is generally contraindicated if a hydatid cyst is suspected, because of the low, but real, risk of anaphylaxis. However, aspiration may occasionally be performed in patients with possible hydatid disease when the diagnosis of amoebic liver abscess remains a possibility, or when the aspiration is performed as part of the therapy. Aspiration should be undertaken only by physicians experienced in performing these procedures and in centres specialised in treating these patients. Careful examination of an aspirate of the cyst can show protoscolices or acid-fast hooklets. [17]
Cystadenoma or cystadenocarcinoma
Clinical manifestations may be absent, or patients may have the insidious onset of abdominal pain, a sense of fullness, and anorexia.Fever and chills are absent.
Ultrasonography or abdominal CT can suggest the diagnosis. Typically appears as a complicated cystic lesion with an irregular thickened wall and occasionally septations within the cyst.Histopathology confirms the diagnosis.
Focal nodular hyperplasia
Patients are usually asymptomatic.
Diagnosis is typically made with combinations of ultrasonography, abdominal CT scan, technetium sulphur colloid scanning, or MRI.
Inflammatory pseudotumours of the liver
Rare benign liver lesion, typically occurring in young men with a history of recent infection.Other associated conditions include inflammatory and autoimmune disorders.Symptoms are similar to liver abscess, although jaundice is more likely to present. [17]
Histopathology shows proliferating fibrous tissue infiltrated by inflammatory cells.
Hepatocellular cancer
Fever is usually absent.
Histopathology confirms the diagnosis.
Secondary liver metastases
Fever is usually absent.There may be signs and symptoms referable to the primary tumour.
Histopathology confirms the diagnosis.

Long QT syndrome

Acquired structural heart disease
History of CAD, MI, or valvular heart disease requiring surgical correction.
Echocardiographic changes consistent with CAD, previous MI, and valvular heart disease. Echocardiography may show regional left ventricular wall motion abnormalities suggestive of infarction and/or scarring. Valvular lesions such as regurgitant and/or stenotic valves in combination with left ventricular dysfunction may be identified by echocardiography.ECG changes consistent with previous MI characterised by presence of Q waves.
Neurocardiogenic (vasovagal) syncope
Triggers include cough, micturition, defecation, swallowing, upright posture, prolonged standing, heat, and hunger.Premonitory symptoms include sweating, feeling hot, and nausea.Recovery period: nausea and vomiting.BP measurement may show orthostatic hypotension, particularly when provoked during a tilt table test.
ECG shows normal QT interval.
Neurological syncope
Triggers include anxiety and stress in panic attack; fatigue, stress, and missed meals in migraine.Premonitory symptoms include hyperventilation, paresthesiae in fingers and lips in panic attack; headache, visual disturbance, sensitivity to light and sound in migraine.
ECG shows normal QT interval.
Catecholaminergic polymorphic ventricular tachyarrhythmias
No differentiating signs or symptoms.History extremely similar to that of LQTS, with arrhythmias triggered by physical activity and emotional stress.
ECG is unremarkable at rest, with no significant prolongation of QT interval.Exercise test provokes PVCs with bidirectional ventricular tachyarrhythmias on ECG.Genetic testing shows mutations in the RyR2 gene in autosomal dominant inheritance and mutations in the CASQ2 gene in autosomal recessive inheritance.
Epilepsy
Triggers include inadequate sleep, alcohol, photic stimulation, drugs.Premonitory symptoms: aura.Syncopal episode: convulsive movement, tongue biting, and incontinence.Recovery period: prolonged postictal state.
EEG shows epileptiform abnormalities.ECG shows normal QT interval.

Lumbosacral intervertebral disc disorders

Musculoskeletal lower back pain
Muscular asymmetry may be visualised, or there may be imbalance or obvious muscle spasm.Palpation of the back may reveal tender points, trigger points, or tight muscle.The straight-leg raise test is negative.
Imaging or laboratory investigations are only performed if there is clinical suspicion of an alternative diagnosis, or when pain is ongoing for more than 4 weeks.
Lumbar facet syndrome
Facet loading (a manoeuver including extension and side bending with rotation to either side) is often painful in facet syndrome but not in situations in which pain has a discogenic origin.Pain radiating across the buttocks and occasionally down the posterior thigh to the knee is suggestive of facet syndrome, whereas pain radiating down the leg beyond the knee is more suggestive of a herniated nucleus pulposus.
Radiographical changes are non-specific for facet joint-mediated pain.The most specific diagnostic test is lumbar medial-branch nerve blockade (LMBB).There is more than 50% pain reduction post LMBB with lumbar facet syndrome.
Lumbar spinal stenosis
Leg pain alleviated by sitting or by a flexed posture.
MRI of the lumbar spine reveals spinal stenosis; hypertrophy of the facet joints and/or ligament flavum with corresponding decrease in spinal canal diameter dimension.
Spondylolysis and/or spondylolisthesis
Mostly asymptomatic; back pain aggravated by extension.Exaggerated lordosis, heart-shaped buttock or midline step-off of the spinous processes may be present.Pain with single-leg hyperextension test. This test is performed by asking the patient to stand on one leg while simultaneously extending the lumbar spine. Pain occurs in the standing leg if spondylitic lesions are present on the same side. However, this is a non-specific test.
Lumbosacral radiographs with AP, lateral and flexion-extension views (to assess for potential instability).Lumbosacral x-rays reveal linear lucency in the pars articularis.Also, x-ray of bilateral hips and pelvis may be considered to detect potential degenerative joint disease of the hips and/or sacrum, causing referral pain.MRI of the lumbosacral spine is typically confirmatory.
Scoliosis
Skeletal pain, deformity.
Skeletal survey radiograph.
Infection (epidural abscess)
Constitutional symptoms (e.g., fevers, chills, weight change, generalised malaise).
WBC count, ESR and CRP are elevated; blood cultures may be positive.
Spinal tumour
Presenting mostly with back or neck pain at night but symptoms may reflect any radicular or myelopathic symptoms.May be no differentiating signs or symptoms.May be a history of neoplasm.
CBC, BUN, ESR, CRP, plain x-rays, CT scan, MRI and bone scan help to make the diagnosis.Biopsy of the spinal lesion will determine the histological tumour type.MRI with gadolinium may reveal enhancement within the bone or epidural space.Further evaluation may include bone scans to look for osseous metastases or PET scans to look for further disease.CT chest, abdomen and pelvis are ordered routinely to evaluate for a primary lesion.
Myofascial pain
Pain and associated spasms in the muscles of the back often manifesting as trigger points.
Infrared or liquid crystal thermography may be used to help diagnose this condition and may show increased blood flow associated with trigger points.Most other investigations are used to rule out other conditions.
Sacroiliac joint pain
Focal pain over the joint.There may be a reproduction of pain with provocative manoeuvers, such as the Gaenslen's manoeuver.This manoeuver is performed by asking the patient to lie supine at the edge of the examination table, and to flex one hip ('bring knee to chest') while extending the other hip over the edge of the examination table ('hang your leg over the table'). Pain in either sacroiliac joint suggests pathology.
The most commonly used diagnostic test is guided intra-articular injection of small-volume local anaesthetic block. The validity of this test has not been confirmed.

Lung abscess

Neoplasm (primary or metastatic lung cancer, lymphoma)
Malignancy is associated with a low-grade fever, absence of leukocytosis, minimal systemic complaints, absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days, and a deteriorating course. [32] Haemoptysis is commonly associated with bronchogenic carcinoma.
CXR: less ground-glass infiltrate surrounding the cavity. View imageSputum cytology: may show malignant cells.CT chest and bronchoscopy: confirm the obstructing lesion.
Tuberculosis
History of exposure to a tuberculosis-infected patient.Systemic symptoms of fatigue, malaise, anorexia, and weight loss, as well as a low-grade fever with night sweats, are prominent.
CXR: cavity is usually located in the upper lobes. View imageSputum smear and culture in Lowenstein-Jensen media: positive for acid-fast bacilli.CT chest: cavitating lesions typically in the upper lobes and usually accompanied by parenchymal infiltrates. Tree-in-bud pattern may be present.
Cavitating pneumonia
Acute, often fulminant infection. Duration of illness before recognition is usually short. Causative organisms include Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes, and Pseudomonas species.
CXR: multiple cavities are usually present. Pleural effusion and empyema are common findings.
Loculated empyema
On respiratory exam, dullness to percussion, decreased breath sounds, and reduced vocal resonance are usually found.
CT chest: empyema appears lenticular in shape, and has a thin wall with smooth luminal margins and a smooth exterior wall. It forms obtuse angles with the chest wall, and shows signs of compression of the uninvolved lung. Separate pleural layers are also seen. [37]
Fungal infection
History of travel to or residence in an endemic area, or occupational exposure.More prevalent in patients with impaired cell-mediated immunity (e.g., AIDS, transplant immunosuppression, malignancies) or granulocytopenia.
Demonstration of typical yeast in fluid or tissue specimens.Culture of pulmonary secretions: positive for fungus.Serological tests: positive for Coccidioides, Histoplasma, or Blastomyces.CXR: typical air crescent sign surrounding the fungus ball in aspergilloma.Aspergillus precipitins: positive in aspergilloma.Serum total IgE and serum-specific IgE to Aspergillus fumigatus allergen: typically elevated in allergic bronchopulmonary aspergillosis and occasionally in aspergilloma.
Nocardiosis
Typically occurs in immunocompromised patients with impaired cell-mediated immunity (e.g., AIDS, transplant immunosuppression, malignancies).
Gram's and acid-fast staining and culture of pulmonary secretions: positive for Nocardia.
Actinomycosis
Manifestations of cutaneous actinomycosis with nodular lesions that tend to form fistulae may be present.
Diagnosis is based on identification of characteristic sulphur granules in pus.Gram's and periodic acid-Schiff staining of histological specimens: presence of actinomycotic colonies.Anaerobic culture of pulmonary secretions: positive for Actinomyces.
Granulomatosis with polyangiitis (Wegener's)
Upper respiratory tract and renal involvement are common. Ocular, cutaneous, musculoskeletal, and neurological manifestations are usually present.
Positive anti-neutrophil cytoplasmic antibody combined with positive specific proteinase 3 antibody testing by enzyme immunoassay.Urinalysis: haematuria and proteinuria.
Rheumatoid lung nodule
Symmetrical arthritis of the small joints of the hands and feet with morning stiffness are common manifestations.
CXR: pulmonary nodules with cavitation usually located in the upper lobe (Caplan's syndrome).Rheumatoid factor: positive.Anti-cyclic citrullinated peptide antibody: positive.

Lyme disease

Tickbite allergy
There is lack of central clearing of the rash.
There are typically no differentiating tests.
Cellulitis
There is a homogeneous, warm, tender, indurated area often accompanied by fever and chills in most cases of cellulitis.
Patients may have leukocytosis or positive blood cultures.
Erythema multiforme
Extensive, disseminated rash often occurs with blistering and mucosal involvement in erythema multiforme major.
Skin biopsy is diagnostic.
Rickettsiosis
Diffuse, generalised maculopapular rash is present in rickettsiosis.
Serology for Rickettsia rickettsii is positive.
Ehrlichiosis
There may be no differentiating symptoms, and ehrlichiosis (anaplasmosis) may cause co-infection in patients with Lyme disease.There may be a history of local prevalence.Absence of rash.
Serology is positive for Ehrlichia species.There may be leukocytopenia.
Babesiosis
There may be no differentiating symptoms, and babesiosis may cause co-infection in patients with Lyme disease.There may be a history of local prevalence.Absence of rash.
Peripheral smear is positive for intraerythrocytic Babesia.There may be evidence of haemolysis.
Tick-borne encephalitis
There may be a history of local prevalence.Absence of rash.Found in Europe.
IgM antibody against tick-borne encephalitis virus is present in cerebrospinal fluid.
Southern tick-associated rash illness (STARI)
Bull's-eye rash on skin after a tick bite from lone star tick (Amblyomma americanum).More commonly reported from different geographical distribution than Lyme disease.Constitutional symptoms including joint pain may occur similar to Lyme disease, but there are no associated neurological, joint, or cardiac sequelae.
Lyme serology is negative in most cases, although there have been a small number of cases where it may be false-positive.A biopsy of skin, identification of the tick as a lone star tick, and a negative Lyme serology aid differentiation.
Chronic fatigue syndrome
Medically unexplained, persistent fatigue, lasting at least 6 months. No reliable biological causes, objective findings, or laboratory anomalies.
A standard battery of laboratory testing is typically normal.

Lymphoblastic lymphoma (LL) NHL

Hodgkin's lymphoma
Bimodal age distribution at diagnosis (peaks at mid-20s and mid-60s), pruritus, and alcohol-triggered pain. Very difficult to differentiate clinically.
Lymph node biopsy (Reed-Sternberg cells are characteristic). [29]
ALL
Acute onset, purpura, bleeding, and infection are key presenting symptoms.
Blood smear (blasts), bone marrow biopsy (blasts), flow cytometry, and immunochistochemistry (tumour cell markers), cytogenetics, PCR.
Infectious mononucleosis
A self-limiting condition that occurs in young adults (high school and university students). There is generally abrupt onset of symptoms including pharyngitis, rash, and myalgias.
Heterophile antibody test (monospot) positive, EBV titres elevated, polyclonal B-lymphocyte population on flow cytometry.
Hepatitis C (HCV)
History of IV drug use, HIV, multiple transfusions; abdominal pain, nausea, symptoms of liver disease and malaise; can be asymptomatic.
Antibody-HCV (enzyme-linked immunosorbent assay [ELISA]) or recombinant immunoblot assay, RT-PCR for HCV RNA.
Cytomegalovirus infection (CMV)
Immunocompromised host (e.g., post-transplant); cough, bone pain, visual symptoms, and diarrhoea are common presenting features.
CMV titres (elevated), CMV PCR, rectal biopsy for CMV.
Tuberculosis
Not always easy to differentiate clinically, but patient may have risk factors for tuberculosis (e.g., HIV positive, history of drug use, inadequate nutrition, inner city population), cough, malaise, and weight loss.
CXR, CT chest, purified protein derivative of tuberculin, acid-fast bacillus test, TB culture, pleural/peritoneal fluid analysis (in some cases), pleural biopsy (in some cases), bone marrow biopsy (in some cases).
HIV infection
Risk factors for sexually transmitted disease (e.g., multiple sexual partners, unprotected sexual intercourse), history of IV drug use, multiple transfusions before 1985, prior flu-like illness and rash.
ELISA (screen), Western blot (confirm), RT-PCR for HIV RNA (viral load) are diagnostic.
Syphilis infection
Consider risk factors for STD; prior genital chancre and rash.
Treponema-non-specific tests: rapid plasma reagin, Venereal Disease Research Laboratory (VDRL); Treponema-specific tests (fluorescent treponemal antibody absorption [FTA-ABS]; micro-haemagglutination Treponema pallidum [MHA-TP]) are diagnostic.
Sarcoidosis
Young or middle-aged, cough, dyspnoea, skin lesions, Bell's palsy, and malaise; may be asymptomatic.
CXR, CT chest (hilar adenopathy), bronchoscopy with biopsy of lymph nodes (non-caseating granulomas).
Rheumatoid arthritis
More common in females; joint symptoms (pain, swelling, heat, stiffness).
Rheumatoid factor (IgM antibody) elevated titre; ESR elevated; synovial fluid analysis.
Systemic lupus erythematosus (SLE)
Much more common in females; characteristic rash (may be butterfly type), photosensitivity, skin lesions, oral ulcers, myalgia, arthritis, and neurological symptoms.
ANA, anti-double-strand DNA, anti-Sm antibodies, abnormal FBC, proteinuria; American Rheumatology Association (ARA) criteria for diagnosis. [30]

Lymphoedema

Chronic venous insufficiency
Damage to the peripheral venous system can lead to lower extremity oedema, usually without significant foot involvement.Pain, ulceration, pitting oedema, pigment changes, and a negative Stemmer's sign are present on clinical evaluation. [28] [4]
Duplex ultrasound: reversed flow; valve closure time >0.5 second indicates reflux.
Deep vein thrombosis (DVT)
May be history of prior DVT, prolonged immobility, or hyper-coaguable state.Usually presents with erythema, warmth, and pain of affected limb.
Duplex ultrasound: presence of a thrombus within the vein.
Lipoedema
Almost always affects pubertal females; typically bilateral and involves the lower extremities while sparing the feet.Physical examination usually reveals limb tenderness, presence of a malleolar fat pad, and a negative Stemmer's sign. [2] [36] [37]
Normal lymphoscintigraphy.MRI scan of affected extremity shows bilateral subcutaneous fat hypertrophy with sparing of the distal extremity.
Obesity
Morbid obesity results in diffuse, excess adipose tissue and therefore patients may have symmetrically enlarged legs secondary to fat deposition.
Normal CT or MRI scan.Normal lymphoscintigraphy. [36]
Congestive heart failure (CHF)
Characterised by generalised pitting oedema that responds to elevation and diuretics. Because CHF is a systemic illness, extremity oedema is typically bilateral, unlike lymphoedema, which is usually unilateral.Additional symptoms include fatigue, light-headedness, poor exercise capacity, and shortness of breath. [4]
ECG may show evidence of underlying CAD, left ventricular hypertrophy, or atrial enlargement. May be conduction abnormalities and abnormal QRS duration.Chest x-ray may reveal pulmonary vascular congestion (vascular redistribution, Kerley's B lines), cardiomegaly (increased cardiothoracic ratio), or pleural effusion (usually right-sided but often bilateral).Echocardiogram confirms the diagnosis.
Hypoalbuminaemia
Renal failure and protein-losing enteropathies cause generalised pitting oedema through reduced intravascular osmotic pressure.Decreased production of protein in hepatic failure similarly leads to generalised pitting oedema.Oedema is therefore bilateral, unlike many patients with lymphoedema, who have one affected extremity.
Low serum protein, low serum albumin, low serum pre-albumin. [4]
Malignancy
Malignant lesions, including lymphangiosarcoma, angiosarcoma, and sarcoma, should be considered when rapid swelling, weight loss, malaise, or pain occurs.
MRI scan and tissue biopsy of affected site confirms the diagnosis.
Klippel-Trenaunay syndrome
Combined lymphatic, venous, and capillary malformation of an extremity with overgrowth. [1]
MRI shows lateral embryonal subcutaneous vein and other venous anomalies. Unlike lymphoedema, malformation involves tissues below muscle fascia.
Haemihypertrophy
Idiopathic enlargement of an extremity is usually a diagnosis of exclusion. [1]
Normal lymphoscintigram. MRI does not show any pathology, only enlarged subcutis, muscle, and bone.

Lymphogranuloma venereum

Syphilis (Treponema pallidum)
Syphilis is in the differential with the presentation of a genital ulcer; however, the primary chancre caused by syphilis differs by its indurated margins, and the associated inguinal lymphadenopathy is usually bilateral and non-tender.
A rapid plasma regain or VDRL test with a confirmatory fluorescent treponemal antibody absorbed test should always be sent as part of a diagnostic work-up for lymphogranuloma venereum (LGV). Dark field microscopy from the swab of a primary syphilitic chancre may also reveal treponemes. [12]
Gonococcal proctitis
Particularly in women and men who have sex with men (MSM) who report a history of receptive anal intercourse, gonococcus is frequently co-transmitted, and though frequently asymptomatic, the acute presentation is very similar to LGV in early stages of proctitis, but LGV progresses to late stages marked by granulomatous inflammation, strictures, and chronic ulcerations. [22]
Diagnosis can be made with swab sent for culture, Gram stain, nucleic acid amplification test or DNA probe for Neisseria gonorrhoeae.
Genital herpes (HSV)
HSV usually presents as painful vesicles that ulcerate; whereas LGV primary ulcers are painless. Genital herpes is also usually associated with bilateral inguinal lymphadenopathy, as opposed to LGV, which tends to be unilateral.
HSV can be isolated by swab in tissue culture or identified by PCR. Cytological changes may also be observed on a Tzank smear. [23]
Chancroid
Chancroid differs from LGV by the predominance of multiple painful papules that rapidly become pustular and exudative.
Gram stain (with Gram-negative rods in a pattern referred to as 'school of fish') and culture for Haemophilus ducreyi are often helpful but the specificity and yield are poor. PCR assays are available. [23]
Granuloma inguinale/donovanosis (Klebsiella granulomatis)
Similar to LGV, ulcerative lesions are painless, but granuloma inguinale spreads subcutaneously and usually progress without true lymphadenitis. Genital lesions are highly vascular, tend to be very friable, and coalesce.
Definitive diagnosis requires visualisation of dark-staining, Donovan bodies on tissue preparation or biopsy. Routine isolation by culture is difficult. [23]
Filariasis
Lymphatic filariasis is in the differential for inguinal lymphadenopathy presenting in endemic regions; however, pruritus and cutaneous manifestations in the extremities suggest parasitic infection rather than LGV.
Micro-filariae that cause lymphatic filariasis can be detected in blood. Nocturnally periodic micro-filariae can be provoked into the blood circulation during the daytime with a dose of diethylcarbamazine if blood testing at night is unfeasible.
Cat-scratch disease (Bartonella henselae)
Though regional lymphadenopathy is the most characteristic manifestation of cat-scratch disease, most patients will report a history of recent contact with a kitten.
Diagnosis may be confirmed by PCR from a lymph node, but in combination with clinical findings, serological testing is the initial test of choice. [24]
Tularaemia (Francisella tularensis)
Tularaemia is usually transmitted by tick or animal exposure. Depending on the portal of entry, tularaemia may present as an ulceroglandular syndrome, but the primary skin lesion is a papule that necroses and leaves behind a painful ulcer. Regional lymphadenopathy may precede, coincide or follow this. In LGV, lymphadenopathy appears after the primary ulcer, which is painless and recedes.
F tularensis can occasionally be isolated from blood, lymph nodes or wounds, but because of the danger to laboratory personnel and its potential use as an agent of bioterrorism, laboratory personnel should be cautioned if suspected. Rapid diagnostic tests are available by serological and PCR assays. [25]
Bubonic plague (Yersinia pestis)
Patients with an inguinal bubo due to plague will usually be acutely ill. Buboes tend to develop rapidly with exquisite tenderness.
Y pestis may be isolated by culture from blood or swabs of skin lesions. Because of the danger to laboratory personnel and its potential use as an agent of bioterrorism, laboratory personnel should be cautioned if suspected. Serological tests are available in patients suspected, but who have negative cultures. [26]
TB (Mycobacterium tuberculosis or disseminated Mycobacterium avium complex)
LGV and TB share the propensity for the formation of chronic sinuses, especially in HIV-positive patients, when extra-pulmonary TB may present with genitourinary, GI involvement or as lymphadenitis (scrofula). Usually systemic mycobacterial infections are associated with haematogenous spread and constitutional symptoms.
A tuberculin test, or purified protein derivative, is usually positive. Biopsy with acid-fast stains of surgical specimens and/or culture is required for definitive diagnosis.
Amoebiasis (Entamoeba histolytica)
In MSM presenting with proctocolitis in endemic regions, E histolytica infection may resemble LGV. [27] Prominent signs and symptoms of invasive disease include diarrhoea, dysentery, and haeme-positive stool.
Diagnosis of amoebic proctocolitis is made by recovery of parasites in the stool.
Lymphoma
Lymphoma will usually be associated with constitutional symptoms and generalised lymphadenopathy.
Diagnosis of lymphoma is made by histopathology from a lymph node biopsy.
Incarcerated inguinal hernia
Differential for an inguinal mass. Hernia most often can be identified by physical examination and manoeuvres to reduce the hernia.
CT scan may be helpful to assess the pelvic anatomy.
Inflammatory bowel disease
Differential for proctocolitis. LGV is generally confined to the distal sigmoid colon and rectum, whereas Crohn's disease may present anywhere in the GI tract. [16]
Histopathology obtained with proctosigmoidoscopy is non-specific and may not help distinguish infection from other inflammatory bowel diseases. [4] Distinction should be made by performing PCR for Chlamydia trachomatis on rectal swab specimen or biopsy.
CMV colitis
Differential for proctocolitis in patients with HIV/AIDS. LGV is generally confined to the distal sigmoid and rectum. [4]
Histopathology obtained with proctosigmoidoscopy may help distinguish CMV. PCR from the serum should also detect a high level viraemia.

Malaria infection

Dengue fever
Abrupt onset of symptoms. Headache and retrobulbar pain that worsens with eye movements is typical. A rash may be present in about half of patients and may be petechial or otherwise haemorrhagic.
Leukopenia and thrombocytopenia are common.PCR may detect dengue virus in serum early in the illness. Isolation of virus by tissue culture is less common. Antibodies may be detected after resolution of the illness but are not helpful in the acute phase.
Pneumonia
Respiratory symptoms prominent, (e.g., cough, haemoptysis, dyspnoea, chest pain).Respiratory examination may reveal focal coarse crackles or consolidation. Hypoxia is common. Signs of pleural effusion may be present (e.g., dullness to percussion, decreased breath sounds over affected area).
Neutrophilia is often present. CRP may be markedly elevated.Chest x-ray may demonstrate infiltrates or consolidation with or without effusion.Sputum culture may reveal the causative organism.Less commonly, blood cultures may be positive for Streptococcus pneumoniae.Urinary antigen testing is available for certain organisms.
Influenza
Important to consider current epidemiological situation, (e.g., pandemics, epidemics, winter months). May give history of ill contacts. Short incubation period (1 to 2 days) with abrupt onset. Mild upper respiratory tract symptoms common (e.g., non-productive cough, pharyngitis, coryza).Wheezing or rhonchi may be audible on auscultation.
Viral culture of nasopharyngeal swabs is disappearing from practice. PCR, often including other respiratory viruses, is commonly used, providing a rapid and sensitive diagnosis.Serological diagnosis rests on demonstrating a change in titre between acute and convalescent samples and is not helpful in the acute period.
Enteric fever (typhoid infection)
Most common on Indian subcontinent. Incubation period 1 to 3 weeks. Gradual onset of sustained fever. Rigors uncommon. Abdominal pain and headache common.Relative bradycardia unreliable. May have a blanching erythematous maculopapular rash (rose spots).
Isolation of Salmonella typhi or S paratyphi in blood, stool, or urine cultures. Occasionally bone marrow culture is necessary.The Widal test is widely used but has poor sensitivity and specificity.
Pyogenic infection
Focal symptoms and signs depend on site affected. May also have prominent systemic symptoms with Group A streptococcal (GAS) infection or pyelonephritis.
Neutrophilia and markedly elevated CRP. Investigations depend on site affected.
Leptospirosis
Conjuctival congestion may be helpful if present. Symptoms and signs of meningitis may be present (e.g., headache, neck stiffness, photophobia). Weil disease is a syndrome of hepatosplenomegaly with jaundice, bleeding diatheses, and renal failure.
Detection of specific IgM response by the end of the first week of the illness. PCR may also be useful.Isolation of leptospires from blood or CSF requires special media and is not routinely done.
Infectious mononucleosis
Clinical syndrome usually caused by Epstein Barr virus (EBV).Characterised by fever, pharyngitis, and lymphadenopathy in older children and young adults.
Peripheral lymphocytosis seen in 70% of cases. [40] Lymphocytes appear atypical on blood film.Heterophile antibodies positive in 90% at some point, but false positives occur.Serology for specific antibodies is widely available and is highly sensitive and specific.
HIV seroconversion
History of unprotected sexual contact or sexually acquired infection. Lymphadenopathy and widespread erythematous rash.
HIV test positive (may be negative in window period).Leukopenia common.
Amoebic liver abscess
Preceding history of dysentery in fewer than 50% of patients. More common in young males.Right upper quadrant pain, possibly referred to the right shoulder. Tender hepatomegaly and right pleural effusion present.
Neutrophilia and elevated alkaline phosphatase.Serology helpful.Stool microscopy may show Entamoeba cysts. Aspirated material contains trophozoites, and PCR is sensitive.Abdominal ultrasound or CT will demonstrate abscess.Chest x-ray may show pleural effusion.
African trypanosomiasis (sleeping sickness)
History of a tsetse fly bite.Detection of a chancre at the site of the bite, and enlarged lymph nodes. There may be a patchy erythematous rash.
Microscopy indicates the presence of trypomastigotes in peripheral blood, lymph node aspirates, or CSF.
Rickettsial infection
May have a history of a tick bite or of spending time on safari.Headache is prominent. May have an eschar or rash.
Possile leukopenia and/or abnormal LFTs.Positive serology, but results will not be available in real time.
Legionnaires' disease
Acquired by inhalation of aerosolised bacteria or, rarely, microaspiration of contaminated drinking water.Presentation includes respiratory symptoms such as cough (may not be productive) and SOB, fever, chills, and chest pain. Other symptoms include headache, nausea, vomiting, abdominal pain, or diarrhoea.
Sputum Gram stain may show gram-negative rods suggestive of Legionella species.Cultures of lower respiratory tract secretions, pleural fluid, lung, blood, or extrapulmonary tissue or fluids show positive growth of Legionella species.Chest x-ray shows a lobar infiltrate.
Pulmonary tuberculosis
Recent travel to endemic area, exposure to TB-infected person.
Sputum cultures with acid-fast bacilli stains positive.A cavity on the chest-x-ray may be observed.

Male factor infertility

Cystic fibrosis (CF)
Thick mucous secretions affect lung and gastrointestinal functioning. Patients often present with failure to thrive and recurrent respiratory tract infections.Men with isolated congenital bilateral absence of vas deferens (CBAVD) with no other clinical signs of CF have a mutation in the CF transmembrane regulator gene in 80% of the cases. [8] If the diagnosis of CBAVD is made, the female partner should be screened for CF.
Neonatal screening for CF is done in many countries.Sweat testing measures the amount of sodium chloride in the sweat. There is excessive loss in CF.Genetic testing is available, but testing is not available for all known gene mutations.
Primary hypogonadism
Testes no longer produce testosterone, resulting in impotence, gynaecomastia, decreased beard and body hair, small testes, and infertility.
Low testosterone level. Elevated FSH and LH.
Hypopituitarism
Partial or complete loss of the functioning of the anterior pituitary gland. If the FSH and LH production is affected, male patients may present with impotence, decreased beard and body hair, small testes, and infertility.
May have decreased LH and FSH.MRI of the pituitary fossa may show a pituitary or hypothalamic lesion.
Pituitary adenoma
A prolactin-producing tumour results in impotence, headaches, and visual disturbance. Galactorrhoea may rarely be present.
Prolactin levels are elevated.MRI shows a tumour in the pituitary gland.
Klinefelter's syndrome
Men have small testes, gynaecomastia, incomplete androgenisation, and infertility due to severe oligozoospermia or complete azoospermia. [12]
Chromosomal analysis shows XXY.
Kartagener's syndrome
Also known as immotile cilia syndrome. Ciliary dyskinesia affects the respiratory tract and spermatozoa. Patients may have a long history of sinusitis, recurrent ear infections, chronic bronchitis, or bronchiectasis.
Diagnosis confirmed on mucosal histological specimen and electron microscopy.
Varicocele
Dilation of the veins of the pampiniform plexus of the scrotum. They occur commonly on the left side. The patient should be examined while standing.
Colour Doppler ultrasound will confirm backflow of blood in the spermatic veins.

Malignant hyperthermia

Non-MH rhabdomyolysis
Electrocardiographic abnormality (peaked T waves and/or bradycardia) evolves into fibrillation prior to the elevation of carbon dioxide tension in blood or end-expiratory gas.
Blood gas and electrolyte measurement.Resolves with treatment of hyperkalaemia with calcium.Muscle histopathology reveals primary muscle pathology.Genetic diagnosis of muscle disease, such as dystrophinopathy.
Muscle disuse atrophy
A history of immobility or neuromuscular injury and exposure to succinylcholine (suxamethonium) is usually present. [33]Electrocardiographic abnormality (peaked T waves and/or bradycardia) evolves into fibrillation prior to elevation of carbon dioxide tension in blood or end-expiratory gas.
Extreme hyperkalaemia can occur after the administration of succinylcholine to a patient with muscle disuse atrophy. Respiratory and metabolic acidosis are usually more marked than hyperkalaemia in a patient experiencing an early MH crisis.Resolves with treatment of hyperkalaemia with calcium.Muscle histopathology may have signs of denervation or necrosis.
Myotonia
Muscle stiffness occurs without a markedly increased metabolism.
Electromyography shows characteristic changes.In some cases genetic testing can be used to diagnose myotonia.
Sepsis
The quality of the muscle tone is different, and shivering may be present.
Responds to antipyretic drugs. The temperature often decreases after paracetamol (acetaminophen) in the presence of infection.Culture of blood, urine, or other material reveals a source of infection.White cell count is elevated.
Complications of laparoscopic surgery
Increased airway pressure is required to maintain minute ventilation but muscle tone is normal.Breath sounds are normal.Crepitus may be present if carbon dioxide has escaped from the body cavity into the skin.
No differentiating tests.
Allergic reaction
Airway oedema, wheezing, and urticaria may be present.
Responds to epinephrine (adrenaline), antihistamines, and steroids.No response to dantrolene.Tryptase and immunoglobulins elevated in blood.Skin testing or blood testing identifies allergen.
Serotonin syndrome
Progression to critical temperature and multi-organ system failure may be slower in than during MH.Triggered by serotonergic drugs rather than inhalation anaesthetics. [34] [35]
Absence of other causes of temperature elevation and rigidity and presence of the drug in the plasma.
Neuroleptic malignant syndrome
Progression to critical temperature and multi-organ system failure may be slower than during MH.Triggered by dopamine receptor antagonists rather than inhalation anaesthetics.
Absence of other causes of temperature elevation and rigidity and presence of the drug in the plasma.
Baclofen withdrawal syndrome
Chronic exposure to baclofen and sudden termination of administration may be followed after several hours with severe dystonia, critical temperature, and multi-organ system failure.
A low plasma or CSF concentration of baclofen.
Thyrotoxicosis
Muscle tone is normal.Increases in metabolism are less marked. [36]Pseudo-hyperthyroidism can be induced by some weight loss dietary supplements.
Blood gas to assess pCO2 and pH is normal.Triiodothyronine (T3) is elevated.
Phaeochromocytoma
Headache and weight loss may be present.Extremities may be cool.
Plasma or urinary catecholamines are elevated.PET scanning of the abdomen and/or thorax reveals the phaeochromocytoma.
Drug-induced muscle injury
A history of the use of known drug triggers (usually statins) is present.Muscle pain and sometimes muscle oedema precede temperature elevation.
No differentiating tests.
Ecstasy overdose
Dehydration is also presentHistory of recent attendance at a 'rave' or ecstasy use is present.
Temperature may decrease after carvedilol administration.
Exertional heat stroke
Hyperventilation and dehydration are present.
Blood gas shows a low pCO2.
Thermal dysregulation
A history of recent exposure to a pyrogen is usually present.
No differentiating tests.
Iatrogenic over-heating
Usually occurs during surgery at small, superficial surgical sites such as the ear when the rest of the patient is covered by occlusive drapes.Administration of heat during anaesthesia.
No differentiating tests.

Mallory-Weiss tear

Oesophagitis
History of oesophageal reflux, systemic disease (e.g., telangiectasias, psoriasis), and recent intake of medications that can induce oesophagitis: for example, immunosuppression, corticosteroid, antibiotics (tetracycline, doxycycline), ferrous sulphate, and ascorbic acid.Physical examination may include the skin, looking for evidence of immunosuppression or systemic disease (e.g., telangiectasias, psoriasis), and the oropharynx, looking for ulcers, thrush, and leukoplakia.Although the patient may be asymptomatic, typical symptoms include odynophagia, dysphagia, retrosternal chest pain, and heart burn, together with 'coffee ground' emesis, anorexia, weight loss, cough, fever, and sepsis.
FBC: may show anaemia.HIV test: may be positive in high-risk patients.Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation, showing irritation/inflammation, brushing, and biopsy of the lesions.
Spontaneous oesophageal perforation (Boerhaave's syndrome)
Classic presentation is an episode of retching or vomiting followed by severe retrosternal pain and/or epigastric pain.History of alcohol intake is obtained in 40% of patients.During physical evaluation, it is important to look for subcutaneous emphysema, which may be absent in 10% to 30% of patients.Other common symptoms and signs include dyspnoea, tachypnoea, cyanosis, sepsis, and shock.
Conventional radiography of the chest may reveal free mediastinal, peritoneal, or prevertebral air. Pleural effusion, with or without pneumothorax, widened mediastinum, and subcutaneous emphysema may be seen in late presentations.Pleural fluid amylase measurement is indicative of oesophageal rupture.Confirmatory tests include the following:Water-soluble contrast (Gastrografin), which is helpful to localise the lesion.CT scan may also be used as a confirmatory test, and findings include oesophageal wall oedema, peri-oesophageal fluid with or without bubbles, and widened mediastinum.Endoscopic evaluation should not be performed in a patient suspected of oesophageal perforation.
Cameron erosions
In an acute setting there is no way to differentiate both entities. However, patients with Cameron erosions may present with symptoms of persistent and recurrent iron deficiency anaemia (weakness, fatigue, dyspnoea). Manifestations of chronic iron-deficiency anaemia include angular cheilitis, glossitis, Koilonychia (spoons nail), and pallor.
FBC: may show anaemia.Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation and biopsy of the lesions. Endoscopic diagnosis of Cameron erosions or ulcers is made when linear erosions or ulcers are seen inside the sliding hiatal hernia.
Peptic ulcer disease
Patients may present with upper GI bleeding or melena, without other symptoms. However, most patients describe a history of gnawing, burning, or hunger-like abdominal pain 40 to 60 minutes after eating, or less often before eating; patients also report nausea, vomiting, weight loss, and fatigue.History of medication use such as aspirin and NSAIDs.Helicobacter pylori is involved in about 60% to 70% of cases of gastric ulcer disease.
Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation, identification of the ulcer, and biopsy of the lesions.Serology tests, urea breath test, H pylori stool antigen test (HpSA), and gastric biopsy may help in the diagnosis of H pylori infection.
Erosive gastropathy
Patients may present with upper GI bleeding or melena and a chronic history of gnawing, burning, or hunger-like abdominal pain accompanied by nausea and vomiting.History of smoking, alcohol intake, and/or medication use, such as aspirin or NSAIDs, is usually obtained.
Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation and biopsy of the lesions. Erosive gastropathy is characterised endoscopically by diffuse hyperaemic mucosa with multiple, small superficial areas of denudated mucosa called erosions.Serology tests, urea breath test, Helicobacter pylori stool antigen test (HpSA), and gastric biopsy may help in the diagnosis of H pylori infection as a cause of the gastritis.
Oesophageal or gastric neoplasms
Patients may present with or without upper GI bleeding (haematochezia, 'coffee ground' emesis with or without melena, and, in rare cases, haematochezia), progressive dysphagia initially for solids and then also for liquids, weight loss, early satiety, unspecific abdominal discomfort, and symptoms of persistent and recurrent iron-deficiency anaemia.
FBC: may show anaemia.Liver function test: may detect liver metastasis.Amylase: usually normal.Lipase: usually normal, elevated in acute pancreatitis; however, lipase is not completely specific for pancreatitis. Lingual, gastric, intestinal, and hepatic isolipases have been isolated.Radiological evaluation may include oesophagogram, upper GI series, or CT scan, each demonstrating an oesophageal or gastric mass.Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation of the mass, brushing, and biopsy of the lesions.
Oesophageal varices
Should be suspected in those with a history of heavy alcohol intake and/or a history of chronic liver disease who present with upper GI bleeding. Physical examination should reveal signs of chronic liver disease (i.e., asterixis, ascitis, pedal oedema, jaundice, splenomegaly, spider angiomas, gynaecomastia, Dupuytren's contractures, leukonychia, and discoloration of the nails indicating hypoalbuminaemia).
FBC: microcytic anaemia and/or thrombocytopoenia.Liver function test: may be elevated in co-existing liver disease.PT/INR: may be elevated in cirrhosis of the liver or liver failure.Oesophagogastroduodenoscopy is the diagnostic and therapeutic test of choice because it allows visualisation of the dilated veins in the lower oesophagus, as well as treatment of the varices.
Arteriovenous malformations
Usually a massive bleeding and should be suspected in patients with a history of abdominal aneurysm or those with a paraprosthetic-enteric fistula, who may give a history of a previous episode of mild 'coffee ground' haematemesis or melena usually self-limited weeks or months earlier (which is called the initial herald or sentinel bleeding).
FBC: may show anaemia.Liver function test: may be deranged in patients with hereditary haemorrhagic telangiectasia of the liver.PT/INR: abnormal value may indicate a less favourable course of the disease.Oesophagogastroduodenoscopy should probably be the first test to be considered to rule out other causes of upper GI bleeding when the diagnosis of aortoenteric fistula is not clear. However, CT scan with contrast is probably the test of choice when aortoenteric fistula is highly suspected.Exploratory laparotomy may allow definitive aortoenteric fistula repair.
Duodenitis
Most patients report chronic, unspecific abdominal pain, which is described as a dull ache, throbbing, burning, or cramping pain that usually comes and goes. Symptoms can be partially relived with antacids. Eating may help or may increase symptoms. Weight loss due to lack of appetite, nausea, and vomiting are common findings.
Oesophagogastroduodenoscopy is the diagnostic test of choice because it allows mucosa visualisation, showing inflammation, and biopsy of the lesions.Serology tests, urea breath test, Helicobacter pylori stool antigen test (HpSA), and gastric biopsy may help in the diagnosis of H pylori infection.

MALT lymphoma

Mantle cell lymphoma
Clinically indistinguishable.
Biopsy specimen shows absence of transformed blasts; expression of CD5, IgD, and nuclear cyclin D1 present on immunohistochemistry, CD23 is negative; t(11;14) demonstrated with cytogenetic testing.
Small lymphocytic lymphoma
Typical clinical features include painless lymphadenopathy, with or without B symptoms. Gastrointestinal disease is uncommon.
Immunohistochemistry shows CD5 and CD23 positivity, while CD10 is negative. The usual cytogenetic abnormalities are del13q14 or trisomy 12.Morphologically, the tumour is also composed of small B cells, but lymphoepithelial lesions and plasma cells are lacking; the presence of CD5 on B cells is a distinguishing feature.Bone marrow biopsy usually demonstrates bone marrow involvement.
Follicular lymphoma
This condition almost always presents with nodal disease. Extra-nodal disease is uncommon.Most patients have widespread disease at presentation, enlarged lymph nodes, and splenomegaly. Occasionally can present with palpable masses in the abdomen and abdominal pain or GI bleeding.
Immunohistochemistry shows CD10 and BCL6 positive tumour cells in and between the follicles.Bone marrow biopsy usually demonstrates bone marrow involvement.
Diffuse large B-cell lymphoma
Symptoms are aggressive, with abdominal pain, vomiting, and haematemesis occurring more commonly than with gastric MALT lymphoma.
Immunohistochemistry reveals medium- to large-sized tumour cells that are CD19-, CD20-, and CD79a-positive with a high proliferative index.
Peptic ulcer disease
Clinically indistinguishable.
Monoclonality may be demonstrated using immunoglobulin gene rearrangement studies in the absence of gastric MALT lymphoma, or precede the development of gastric MALT lymphoma.
Hashimoto's thyroiditis
Causes hypothyroidism that is usually insidious in onset, with signs and symptoms slowly progressing over months to years.Some of the common symptoms of hypothyroidism include cold intolerance, voice hoarseness and pressure symptoms in the neck from thyroid enlargement, slowed movement and loss of energy, menstrual irregularities (typically menorrhagia, infertility, and loss of libido), depression, dementia, and other psychiatric disturbances, as well as memory loss.
Elevated TSH with low free T4 levels; antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies are positive in the majority of cases.
Lymphoepithelial sialadenitis
Clinically indistinguishable.
Biopsy of the salivary glands shows a spectrum of histopathological features including: 1) fully benign lymphoid infiltrate, with or without an associated lymphoid follicular structure, without immunoglobulin (Ig) light chain restriction in B-cells, and without any features of aggressive behaviour; 2) lymphoproliferative lesions, with or without areas of Ig light chain restriction in B-cells, with the usual presence of centrocyte-like cells. A more or less pronounced lymphoepithelial aggressiveness may be present without definite evidence of malignancy.B-cell clones are detected in over 50% of cases by molecular genetic methods but this does not correlate with morphological or clinical evidence of overt lymphoma.

Marfan's syndrome

Aortic dissection not associated with Marfan's syndrome
No eye or musculoskeletal findings.Relevant family history in familial dissections.
No differentiating tests.
Bicuspid aortic valve
No eye or musculoskeletal findings although occasionally occurs with Marfan's syndrome.
Echo, thorax CT or thorax MRI will show abnormal bicuspid aortic valve.
Ehlers-Danlos syndrome
Joint hypermobility more common presentation.Type IV variety, which most commonly affects the aorta, is characterised by thin skin and bleeding disorders with increased bruising.
Skin biopsy for abnormal collagen and DNA testing for gene mutation.
Erdheim's deformity
Flask-like root dilatation of the aortic root as in Marfan's syndrome but no eye or musculoskeletal findings or family history.
No differentiating tests.
Homocystinuria
Signs and symptoms very similar.Generalised osteoporosis and disorders of mental development more likely in homocystinuria.
Plasma homocystine levels are elevated.
Loeys-Dietz syndrome
No associated lens dislocation.Aortic dissection occurs at much smaller diameter. [15]Bifid uvula or cleft palate.Arterial tortuosity.Hypertelorism.
Not currently available.

Mastitis and breast abscess

Breast engorgement
Engorgement usually occurs on the third to fifth post-partum day.There may be bilateral generalised breast pain, firmness, erythema, warmth, and a mild fever (milk fever), but there is usually no oedema.Relieved by frequent emptying of the breasts (e.g., breastfeeding).
Usually becomes clinically apparent as breastfeeding continues.
Nipple sensitivity
There is usually no evidence of nipple trauma, features of breast inflammation, or fever.Nipple vasospasm (Raynaud's phenomenon) may manifest with nipple pain.Nipple sensitivity with breastfeeding usually subsides once suckling begins, whereas pain from trauma or infection persists or increases.
Usually becomes clinically apparent as breastfeeding continues.
Galactocoele
A milk retention cyst may cause a tender palpable breast lump, but there are usually no sharp shooting pains and no signs of breast inflammation or systemic illness.
A galactocoele appears on ultrasound as a well-defined lesion with a thin echogenic wall, which may contain coarse calcification. A breast abscess may also be well circumscribed, macrolobulated, irregular, or ill defined with possible septae.Galactocele aspiration yields non-purulent milk.
Fibrocystic breasts
Painful breast tissue before menses improves during menstruation.Lumps are palpated mainly in the upper outer quadrant.A non-bloody nipple discharge may be reported.
Ultrasound may help to diagnose benign cystic breast tissue.Mammography is only indicated to help with diagnosis of fibrocystic disease in older women, not adolescents, because the density of breast tissue in adolescents makes interpretation difficult.
Mastodynia
Mastalgia may be cyclic or non-cyclic with menstruation.There should be no symptoms or signs of breast inflammation.
Specific tests are not indicated.Diagnosis is based on history and examination.
Breast trauma
Trauma may cause fat necrosis, which could manifest as a breast mass.Signs of inflammation are uncommon.
Imaging studies may mimic carcinoma (as also occurs on occasion with breast infection).A biopsy may be indicated for a definitive diagnosis.
Primary invasive breast cancer
The signs and symptoms of breast cancer may be similar to those of breast infection.It may present as a hard, irregular, painless mass that may or may not be fixed to the underlying tissue.There may be a nipple discharge, nipple or skin retraction, skin oedema (peau d'orange), and regional lymphadenopathy. Paget's disease will involve the nipple.Inflammatory breast cancer may resemble mastitis with breast enlargement, warmth, tenderness, oedema, erythema, and possible skin discoloration.
Imaging studies, such as mammography, may reveal a mass, increased density, and micro-calcification.Percutaneous biopsy (recommended method), or surgical excision (excisional biopsy) if indicated, is necessary to establish the diagnosis.A skin-punch biopsy for inflammatory breast carcinoma will show tumour infiltration of dermal lymphatics.
Fibroadenoma
Presents typically as a non-tender, rubbery, well-circumscribed, and mobile mass.
Imaging studies, such as breast ultrasound and mammography, generally reveal a solid, homogeneous, well-circumscribed, avascular mass with occasional coarse calcification.Pathological examination will demonstrate a fibroepithelial lesion.
Fat necrosis
Typically results in a tender, round, firm breast mass.The skin may be dimpled over such a lump.Inflammation is usually not a common feature unless there is an associated infection.
Breast imaging findings may not be specific.A breast biopsy is the most accurate means of providing a definitive diagnosis.
Diabetes
May manifest with one or more hard, irregular, mobile, discrete, painless, palpable masses.Complications arising from diabetes such as retinopathy, neuropathy, and nephropathy may be present.Breast lesions tend to be recurrent and bilateral.Patients may have other autoimmune diseases.
Breast imaging studies may be non-specific and can mimic cancer.Biopsy shows sclerosing lobular lymphocytic mastitis.
Mondor's disease
Thrombophlebitis of a superficial vein may cause breast pain and a cord-like mass with possible skin dimpling, usually in the lower quadrants.The cord is accentuated by traction, elevation of the breast, or abduction of the ipsilateral arm.
Mammography and a microbiology work-up are usually negative.
Systemic lupus erythematosus
A history of SLE is highly suggestive.There may be a tender mass lesion with possible skin changes.Chronic mastitis with flares may be reported.
Serological evidence of lupus is usually present.Mammography may show architectural distortion, fat necrosis, or calcifications. [42]A biopsy may help, showing lupus panniculitis.
Necrotising fasciitis
Patients may have fever, chills, and extreme pain associated with rapidly advancing skin erythema, and possible cyanosis, vesicles, bullae, ulcers, crepitation, and a black necrotic eschar.Examination by an experienced surgeon is critical.A history of prior trauma, skin biopsy, or a surgical wound in the mammary region may be reported.
Laboratory tests may show leukocytosis, elevated urea, and reduced serum sodium level.Infection can be diagnosed with rapid streptococcal diagnostic kits, if available.Microbiology studies and excisional deep skin biopsy may be helpful in diagnosing and identifying the causative organisms and confirming the diagnosis.
Hidradenitis suppurativa
Presents mainly around hair follicles in the axilla and intertriginous regions under the breasts.Lesions range from comedones to painful lumps, abscesses, and skin scarring, and these may be associated with a purulent discharge.
A biopsy will show acute and chronic folliculitis with a possible foreign body giant cell inflammation.
Costochondritis
There is localised sternal pain, often exacerbated with respiration or activity.Pain may radiate.A palpable swelling with redness is often located about 4 cm from the sternal edge.A breast examination is usually unremarkable.
Tests are not necessary.
Neonatal breast hypertrophy
Benign breast enlargement may be transient.The breast bud in such cases is not red or tender.If present, a nipple discharge is milky and not purulent.
Tests are not necessary.
Gigantomastia
Massive hypertrophy of the breasts may occur early in pregnancy.There may be associated skin necrosis.
Microbiology studies may be required to exclude underlying infection.

Measles infection

Rubella
Typically a mild illness with patient and rash improving in about 3 days; no Koplik's spots.
Rubella specific IgM antibody or other specific test for rubella.
Parvovirus B19
Typically a mild illness, associated classically with rash initially presenting with 'slapped cheek' appearance, followed by lacy, reticular lesions; may have associated arthritis and/or anaemia. Fever has usually subsided before rash develops. No Koplik's spots and occurs much more commonly than measles.
Parvovirus specific antibody detection.
Roseola
No Koplik's spots. Rash appears after fever breaks.
Specific test for human herpes virus 6 or human herpes virus 7.
Dengue
No Koplik's spots. Febrile illness in which headache and body aches are prominent. Rash may be petechial. Appropriate exposure including exposure to mosquitoes that may carry dengue.
Specific test for dengue antibody.
EBV infection (mononucleosis)
No Koplik's spots. Febrile illness that may involve sore throat, pharyngeal exudates and hepatosplenomegaly.
Specific test for EBV antibody. Monospot for children over age 4 years.
Drug eruptions
History of recent medication or drug ingestion.
No differentiating tests.

Meckel's diverticulum

Appendicitis
Typically presents as acute abdominal pain starting in the mid-abdomen and later localising to the RLQ. Associated with fever, anorexia, nausea, vomiting, and elevated neutrophil count.May be clinically indistinguishable from Meckel's diverticulitis.
CT scan shows a dilated appendix, and periappendiceal inflammatory changes, such as fat stranding of the mesoappendix or adjacent retroperitoneal fat. [26]
Non-MD-related intussusception
Typically presents between 5 and 7 months of age with vomiting; older children also complain of abdominal pain. Often a history of progressive lethargy, and there may have been a recent viral illness.A palpable abdominal mass or abdominal distention may be found on examination.May be clinically indistinguishable from Meckel's diverticulitis.
Plain abdominal x-ray reveals intestinal obstruction and paucity of gas in the RLQ, as well as often showing the characteristic 'target sign'.Abdominal ultrasound may establish the diagnosis, but contrast enema (air or contrast reagent) is the most specific and sensitive test for diagnosis, and it may be therapeutic.
Biliary colic
Pain and tenderness, usually in the RUQ and sometimes associated with nausea and vomiting.Pain is most commonly triggered by fatty foods, but it can also be initiated by other types of food, or it can occur spontaneously.
Abdominal ultrasound has a high specificity (>98%) for the diagnosis of cholelithiasis and a negative predictive value of 95% for the diagnosis of cholecystitis. [27]
Infectious colitis
Diarrhoea is often present; it may be associated with lower abdominal discomfort or cramps.May give a history of sick contacts and travel to an area where infectious colitis is endemic.
Stool samples are tested for infectious aetiology.CT scanning is useful to evaluate for thickened, inflamed loops of large bowel.
Colonic diverticulitis
Occurs in adults, mostly >40 years of age.LLQ pain, fever, malaise, and leukocytosis.
CT scan is test of choice for symptomatic diverticulitis.
Gastroenteritis
Common in children.Characterised by nausea, vomiting, and diarrhoea, along with crampy abdominal pain.Abdominal examination does not identify any localising signs.
Clinical diagnosis.
Crohn's disease
Chronic diarrhoea, weight loss, and RLQ abdominal pain mimicking acute appendicitis.
Diagnosis confirmed by colonoscopy with ileoscopy and tissue biopsy. [28]
Ulcerative colitis
Typically presents in young adults.Diarrhoea, often bloody, with faecal urgency and crampy abdominal pain localised to the RLQ or LLQ.Course may be relapsing-remitting.May have extraintestinal manifestations, such as erythema nodosum and acute arthropathy.
Diagnosis requires, at a minimum, negative stool culture and sigmoidoscopy or colonoscopy. [28]Tissue biopsy required for confirmation of diagnosis.
Irritable bowel syndrome
Non-specific abdominal pain, bloating, and disturbed defecation.
FBC, stool cultures, and colonoscopy exclude organic disease.
Necrotising enterocolitis
Most commonly occurs in premature infants.
Abdominal radiographs often demonstrate gas within the intestinal wall (pneumatosis intestinalis).
Peptic ulcer disease
Chronic, upper abdominal pain (often epigastric) related to eating a meal (dyspepsia).Epigastric tenderness may be present, but often there are no other signs on physical examination.
Upper GI endoscopy is diagnostic and may show an ulcer in the stomach or proximal duodenum.

Meconium aspiration syndrome

Transient tachypnoea of the newborn
May be seen in infants of any gestational age. Hx of maternal diabetes may be present. Most infants of diabetic mothers are macrosomic. Tachypnoea is the main feature with no hypoxia or cyanosis. Hx of meconium-stained amniotic fluid (MSAF) may or may not be present.
CXR is the most important distinguishing test. Findings include perihilar markings and presence of fluid in the transverse fissure on the right side (sail sign). Absence of atelectasis.Arterial blood gas (ABG) measurement shows no evidence of hypoxaemia or acidosis.
Surfactant deficiency
Respiratory distress secondary to surfactant deficiency is more common in preterm and late preterm infants. A variant of surfactant protein B deficiency may be present as severe respiratory distress in late preterm and term infants, leading to typical clinical presentation of respiratory distress syndrome/hyaline membrane disease; absence of hx of MSAF.
Demonstration of absence of surfactant protein B deficiency by molecular testing.ABG measurement shows severe hypoxaemia and acidosis.
Persistent pulmonary hypertension
May be present in association with MAS. Persistent hypoxaemia is present despite maximum ventilator support.
Pulse oximetry demonstrates differential oxygenation between preductal and postductal sites with low oxygen saturation as measured by pulse oximetry. A difference of >5% to 10% in saturation indicates right-to-left shunt through the ductus arteriosus. However, when the saturation is below normal in both sites, absence of difference does not rule out persistent pulmonary hypertension.A difference in PaO2 of 20 mmHg also indicates presence of right-to-left shunt.CXR may show no severe parenchymal disease.Echocardiography reveals tricuspid regurgitation, elevated pulmonary artery pressure, and right-to-left shunt through patent ductus arteriosus and patent foramen ovale.
Cyanotic congenital heart disease
Infants are usually term in gestation. Minimal respiratory disease but severe cyanosis that does not respond to giving 100% oxygen. No hx of MSAF or birth asphyxia.
Echocardiography helps to establish the correct diagnosis of cyanotic heart disease in the newborn.
Lung hypoplasia
Hx of chronic leakage of amniotic fluid and oligohydramnios; hx of difficult resuscitation in the delivery room. Severe hypoxaemia is present. There may be hx of MSAF with thick or thin meconium.
CXR shows small lung volumes.ABG measurement shows severe hypoxaemia.Echocardiography shows absence of congenital cyanotic heart disease and presence of severe persistent pulmonary hypertension.
B streptococcus infection/pneumonia
Hx of B streptococcus sepsis in a sibling or positive B streptococcus culture in the mother before delivery without intrapartum antibiotics; hx of prolonged rupture of membranes. It is usually associated with hypotension. Signs of shock may be present.
FBC findings include severe leukopenia and thrombocytopenia.ABG shows persistent metabolic acidosis.Blood culture is positive for B streptococcus infections.
Amniotic fluid aspiration
Aspiration of amniotic fluid before birth with hypoxia or asphyxia. No differentiating signs or symptoms.
Diagnosis is by history, clinical observation, and a positive blood culture for infection.
Blood aspiration
Stomach contents may be aspirated during vaginal or caesarean birth. Occurs at birth in the presence of placental abruption or placenta previa.No differentiating signs or symptoms.
Diagnosis is by history, clinical observation, and a positive blood culture for infection.
Aspiration pneumonia
Usually occurs after birth and involves aspiration of gastric contents. It can occur with gastro-oesophageal reflux or swallowing dysfunction.No differentiating signs or symptoms.
Diagnosis is by history, clinical observation, and a positive blood culture for infection.

Medial collateral ligament injury

Medial meniscus tear
Patients frequently complain of mechanical symptoms in their knees such as catching, giving way, locking, clicking, and popping; these symptoms are unusual in isolated MCL injuries.May present with quadriceps atrophy and often have an associated knee effusion and tenderness localised to the joint line. In contrast, MCL injuries have tenderness above and below the joint line following the path of the MCL. The McMurray test can be used for diagnosing meniscal injury. It is performed with the patient lying supine and the examiner placing one hand on the lateral joint line, providing a valgus stress. If pain or a click is felt as the knee is externally rotated and brought into full extension, the examination is positive and suggestive of a medial meniscal tear. The McMurray test has a low positive predictive value (82.6%) and therefore has a limited role in clinical practice. [24]
MRI is the most accurate test. MRI reports score the quality of the meniscus signal on a 0-III scale: grade 0 represents normal, healthy meniscus and grade III represents a torn meniscus.Diagnostic ultrasound of the knee may also be useful in visualising pathology.
Soft tissue contusion of the medial knee
Patients usually describe an object impacting the knee.Absence of valgus laxity on abduction stress testing.
MRI or ultrasound will show oedema surrounding the contusion but should demonstrate an intact MCL with normal-appearing fibres.
Tibial plateau fracture
Usually involves a large force on the knee, commonly seen in major falls or motor vehicle accidents.Significant pain, effusion, and joint stiffness symptoms.
Plain x-rays in multiple obliquities of the knee (anteroposterior, lateral, patellofemoral, and oblique) will usually reveal a disruption of the tibial articular surface.CT provides a more detailed view of the pathology.
Osteochondral fracture
Immediate pain and swelling of the knee at the time of injury. Significant pain with weight-bearing.Mechanism of injury usually involves a high-force, twisting injury of the knee.
Osteochondral fractures may be missed on x-rays. CT and MRI are preferred as they provide more detailed images.
Pes anserinus bursitis
Tenderness along the medial knee that worsens when patients go up and down stairs. Pain is usually absent when walking on a level surface.Unlike MCL sprains, there is usually no history of acute injury.Tenderness at the conjoint tendons of the pes anserinus, located 3 to 5 cm below the anteromedial margin of the knee.No valgus laxity on abduction stress testing.
T2-weighted MRI images demonstrate an increase in signal intensity in the pes anserinus bursa.

Medullary sponge kidney

Distal renal tubular acidosis
Rarely symptomatic, but patients may have a hx of renal calculi or nephrocalcinosis.
Urine pH ≥6.3 on urinalysis with normal anion gap metabolic acidosis is indicative of distal renal tubular acidosis (dRTA). However, dRTA can occur in MSK.Serum bicarbonate is the most sensitive and specific test for most forms of RTA. The finding of low serum bicarbonate concentration is the usual starting point for investigating metabolic acidosis.
Renal papillary necrosis
Nocturia, polyuria; haematuria, flank pain, pyelonephritis. Rarely renal dysfunction.
Passage of sloughed tissue in urine.Increased serum creatinine reflecting chronic kidney disease may be seen.Low specific gravity on urinalysis or low urine osmolality during water deprivation.
Tuberculosis of kidney
Hx of tuberculosis.Hx of both upper and lower tract collecting system involvement.
Positive urine mycobacterial culture, positive tuberculosis skin test.Intravenous urography shows calyceal blunting, papillary necrosis ureteral strictures, and bladder, vas deferens, seminal vesicle, or prostate calcifications.
Polycystic kidney disease
Patients may have hypertension, which is not classically seen with MSK.Progressive chronic kidney disease may be present, whereas this is extremely rare for MSK.
Polycystin 1 or 2 gene mutation.Cortical cysts seen on CT or ultrasound.Urea and creatinine may be elevated.

Medulloblastoma

Migraine
Family history of migraine.Aura may be present.Headache does not occur daily and is not worse in the morning.
Neuroimaging of the brain will be normal.
Viral infection
Sick contacts at home or school.Associated with fever, myalgias, arthralgias, diarrhoea, or rhinorrhoea.Vomiting not just in morning; symptoms do not improve after vomiting.
Blood work shows elevated WBC.Neuroimaging of the brain will be normal.
Ependymoma
Ataxia more common.
tumour in region of foramen of Luschka on MRI.Calcifications on brain CT. [27]Biopsy of lesion confirms diagnosis.
Juvenile pilocytic astrocytoma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Cystic with enhancing nodule. [27]Biopsy of lesion confirms diagnosis.
Fibrillary astrocytoma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Biopsy of lesion confirms diagnosis.
Ganglioglioma
Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar hemisphere and not growing into or filling the fourth ventricle on neuroimaging, but can be effacing the ventricle, an important distinction. [27]Biopsy of lesion confirms diagnosis.
Atypical teratoid/rhabdoid tumour
Very difficult to distinguish from medulloblastoma. Presents similarly, with signs and symptoms of obstructive hydrocephalus.
Originating in the cerebellar vermis and growing into and filling the fourth ventricle on neuroimaging. [27]Very difficult to distinguish from medulloblastoma.Similar histology to medulloblastoma; however, immunohistochemistry will show absence of staining for the product of the tumour suppressor gene INI-1. [31]

Melanoma

benign melanocytic naevi
Benign melanocytic naevi tend to be smaller than melanomas, with an absence of colour variegation or marked asymmetry/border irregularity and no clinical features of regression (loss of colour with a bluish-white veiled appearance). In addition, benign melanocytic naevi do not change or demonstrate spontaneous ulceration or bleeding such as that seen in melanoma.
Difference in appearance on dermatoscopic evaluation. The diagnostic test is skin biopsy.
seborrhoeic keratosis
Seborrhoeic keratoses demonstrate a waxy, 'stuck on', often hyperkeratotic appearance, with surface horned cysts.
Difference in appearance on dermatoscopic evaluation, with presence of horned cysts and hairpin-shaped blood vessels in seborrhoeic keratoses.The diagnostic test is skin biopsy.
pigmented basal cell carcinoma
Basal cell carcinoma will have a pearly appearance with less pigmentation than a typical malignant melanoma.In addition, there are prominent branching telangiectatic vessels in basal cell carcinoma.
Difference in appearance on dermatoscopic evaluation, with leaf-like areas of pigmentation and arborising blood vessels in pigmented basal cell carcinoma.The diagnostic test is skin biopsy.
pigmented actinic keratosis
Pigmented actinic keratoses demonstrate more hyperkeratosis and erythema than melanoma, with less pigmentation, and tend to be somewhat smaller in size.Pain may be associated with pigmented actinic keratoses.
The diagnostic test is skin biopsy.
dermatofibroma
Dermatofibroma demonstrates skin dimpling on palpation and a scar-like appearance, and is typically localised to the extremities only.
Dermatoscopy displays a difference in appearance, with a central scar-like area present in dermatofibroma. [59]The diagnostic test is skin biopsy.
subungual haematoma
Instead of a longitudinal band, often associated with a subungual melanoma, a subungual haematoma appears as reddish-black globules of pigment that grow out distally as the nail grows.In addition, the patient may be able to give a history of prior trauma.Subungual melanoma may demonstrate pigmentation extending onto the proximal nail fold (Hutchinson's sign), unlike a subungual haematoma.
Difference in appearance on dermatoscopic evaluation, with presence of homogenous brownish-red pigment with multiple globules and an absence of melanin granules. [60] Scrapings of pigment can be tested with a urinalysis strip to detect blood. [61] However, tumours such as melanoma may be associated with subungual bleeding. [62]The diagnostic test is skin biopsy.
intracorneal haematoma
Haemorrhage in the stratum corneum may be accompanied by a history of trauma.
The pigment can be pared away with a number 15 scalpel blade.
tinea nigra
Superficial infection of the stratum corneum that typically appears on the palmar surface of the hands or feet. Usually not itchy. More homogenous pigmentation is seen than in malignant melanoma.
The pigment can be pared away with a number 15 scalpel blade. Skin scrapings show septate hyphae on KOH microscopic examination.
pyogenic granuloma
A lobular haemangioma most commonly seen in children. A mucosal form (usually affecting the maxillary mucosa or the inner nose) is commonly seen in pregnant women.A new lesion is typically bright red in colour, which pales to a fleshy pink colour with time.
The diagnostic test is skin biopsy.

Melasma

Exogenous ochronosis
Skin hyperpigmentation associated with use of the bleaching agent hydroquinone. It is caused by the deposition of polymerised homogentisic acid in the skin.Historically, this condition follows use of hydroquinone products, and distribution correlates with areas of medicine application.Most commonly seen in people with Fitzpatrick type V or VI skin who have used hydroquinone-containing preparations of >3% concentration for months to years, and who have had significant UV light exposure without the use of photoprotection.
Skin biopsy shows golden-yellow to brown deposition of pigment in the dermis.
Post-inflammatory hyperpigmentation
Hyperpigmentation of skin that was previously inflamed due to dermatitis.Diagnosis is typically made on history of erythema, pruritus, and dermatitis preceding the hyperpigmentation.
Diagnosis is clinical.
Phototoxic reaction
Seen in patients exposed to systemic or topical medicines or cosmetics, and then UV radiation.Disease usually begins abruptly, in contrast to melasma, which develops gradually.
Diagnosis is clinical.
Riehl melanosis
Facial hyperpigmented contact dermatitis due to the use of facial cosmetics. [15]Typically distribution is patchier than classic melasma and resolves when offending agent is discontinued.
Patch testing can be done to look for reaction to components of cosmetics.
Erythema dyschromicum perstans
Also called ashy dermatosis. Most frequently seen in Hispanic people and can be seen at any age.Clinically, it presents as multiple blue-grey macules on the neck, chest, and sometimes the face.The colour and distribution, as well as the lack of association with UV light exposure, help to differentiate it from melasma. [16]
Skin biopsy is non-specific, but can show some cell death at the dermal-epidermal junction, as well as pigment incontinence. [16]

Membranous nephropathy

Focal segmental glomerulosclerosis
More common in black people. Clinically indistinguishable, as presents with nephrotic syndrome characteristics.
Renal biopsy shows glomerulosclerosis on light microscopy in a focal and segmental pattern. Immunofluorescence usually negative.
Minimal change disease
More common in children. Clinically indistinguishable, as presents with nephrotic syndrome characteristics.
Electron microscopy of biopsy shows diffuse podocyte effacement. Light microscopy and immunofluorescence normal.
Mesangioproliferative glomerulonephritis
Presents with nephrotic syndrome. Haematuria may also be present.
Renal biopsy; light and electron microscopy show pattern of cellular proliferation; immunofluorescence microscopy may show patterns of immune complex deposition.Complement levels more commonly low, and cryoglobulins may be present.
Amyloidosis
Can affect other organ systems such as heart and peripheral nerves. Hypotension may be present.
Light microscopy reveals glomerular amyloid deposits with Congo red staining under polarised light. Electron microscopy shows deposition of protein fibrils.
Diabetic nephropathy
Hx of diabetes.
Renal biopsy: mesangial expansion, fibrosis, and classic Kimmelstiel-Wilson nodules.

Memorial Sloan-Kettering New York 2 protocol for ALL relapse

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Meniere's disease

Acoustic neuroma
Small acoustic tumours typically present as unilateral high-frequency hearing loss with difficulty hearing on the telephone on affected ear.Acoustic neuroma should be ruled out in any unilateral sensorineural hearing and therefore in patients with MD. [29]
There is reduced word recognition score to an inordinate degree when compared with pure-tone air and bone conduction testing (phonemic regression), roll-over phenomenon, absent or elevated acoustic reflexes, abnormal findings on stapedial reflex decay, and abnormal auditory brainstem response.Hearing tests may be within normal limits in patients with small acoustic neuromas.MRI with gadolinium contrast will show a tumour involving the acoustic nerve.
Vestibular migraine (also called migraine-associated dizziness and migraine-associated vertigo)
Incidence of migraine is significantly greater in populations of MD patients, and incidence of complaints of dizziness and MD is greater in migraine populations, than ithe incidence of either in the general unselected population. [30]Symptoms and clinical test findings produced by both disorders overlap, and both conditions can co-exist in the same patient.A very short (<15 minutes) or prolonged (>24 hours) duration of vertigo suggests migraine, and visual auras are more likely. Hearing loss is usually mild and stable over time.
Investigations are variable and non-specific. Diagnosis is made on clinical history. [30]
Vestibular neuronitis
Neural degeneration or viral infection of the eighth nerve can produce acute or chronic vertigo, nausea, and vomiting. There is no hearing loss, tinnitus, or aural fullness.Occurs in epidemics and is most common in people between 40 and 50 years of age. Frequently, patients have had a recent viral infection.Attacks are of precipitous onset, often occurring at night. Severe rotational vertigo lasts 12 to 36 hours with decreasing disequilibrium for the next 4 to 5 days.
Electronystagmography (particularly using bi-thermal caloric testing) often shows unilateral weakness on the affected side, but may be normal.
Viral labyrinthitis
Similar presentation to vestibular neuronitis but accompanied by hearing loss and tinnitus. [31]
Patients show various degrees of hearing loss on complete audiological evaluation.
Benign paroxysmal positional vertigo (BPPV)
Patients typically present with episodic vertigo lasting in the range of a few seconds to a minute elicited by certain head movements. These movements include lying flat with the neck extended and turned towards the affected ear, neck extension, and bending over. Unlike attacks caused by MD, the vertigo spells are not associated with hearing loss, tinnitus, or aural fullness. The vertigo could recur over a period of weeks to months and may resolve spontaneously. Patients usually report a history of trauma or vestibular neuritis. It is important to note that BPPV and MD have been reported to co-exist in the same patient. [32]
Hallpike's test will show rotatory nystagmus on the affected side. This is performed by starting in the sitting position then bringing to a supine position with the head turned 45° towards one side with 20° neck extension. Patients with BPPV usually demonstrate a short-lasting torsional nystagmus in this position. [33]
Vertebrobasilar insufficiency
Cerebrovascular disease is more common in older people. The vertigo might be secondary to ischaemia of the labyrinth, brain stem, or both, since they are all supplied by the vertebrobasilar circulation. [34]Vertigo spells usually last for several minutes, and are accompanied by nausea, vomiting, and severe imbalance. Associated symptoms may include visual blurring or black-outs, diplopia, drop attacks, weakness and numbness of the extremities, and headache. [34]
Carotid duplex ultrasound may show changes of atherosclerosis, which implies changes in the cerebral circulation.CT head may show evidence of previous cerebral infarction.Magnetic resonance angiography of vessels of neck, base of skull, and circle of Willis may be abnormal.

Meningioma

Dural metastasis
History of previous cancer (especially breast).
Biopsy would reveal histological evidence of metastatic tumour.
Granuloma
Possible systemic symptoms consistent with sarcoid or tuberculosis.
CXR and serum biochemistries often abnormal.
Pituitary adenoma (in appropriate parasellar location)
Possible hypersecretory symptoms in pituitary tumour.
Hormonal studies, such as prolactin, growth hormone, cortisol, TFTs, and gonadotrophins, may indicate hyper- or hypo-secretion.
Schwannoma (especially in spine or at skull base)
Possible radicular neurological deficit or cranial nerve deficit.
Biopsy would reveal characteristic Antoni A and Antoni B histological features.
Skull base lymphoma
None.
Bone marrow biopsy; may be negative if primary CNS lymphoma.

Meningococcal disease

Streptococcus pneumoniae sepsis
Purpura fulminans is more characteristic in meningococcaemia than in sepsis caused by other bacterial pathogens.
Blood or other body fluid cultures diagnostic.
Staphylococcus aureus sepsis
Purpura fulminans is more characteristic in meningococcaemia than in sepsis caused by other bacterial pathogens.
Blood or other body fluid cultures diagnostic.
Streptococcus pyogenes sepsis
Purpura fulminans is more characteristic in meningococcaemia than in sepsis caused by other bacterial pathogens.
Blood or other body fluid cultures diagnostic.
Streptococcal pharyngitis
Pharyngeal erythema and, frequently, tonsillar exudates and tender cervical adenopathy. Although the onset is abrupt, the infection does not progress rapidly.
Throat culture or antigen detection is positive for beta-haemolytic S pyogenes.
Gonococcaemia
Typically presents with septic arthritis, tenosynovitis, and tender pustular skin lesions. Infections are most common in women and often begin within a week of the start of a menstrual period. Unlike meningococcaemia, disseminated gonococcaemia rarely progresses rapidly.
Urethral, cervical, rectal, and oropharyngeal cultures, nucleic acid amplification tests, or blood cultures indicate gonococcal infection.
Leptospirosis
The disease course may be bimodal, with fever, meningitis, and a rash, which may be haemorrhagic, developing several days after improvement in initial symptoms. Hepatitis, jaundice, interstitial nephritis, and myocarditis are common in severe Leptospira infections but are rare in meningococcal infections.
Serological testing confirms leptospirosis.
Rocky Mountain spotted fever (RMSF)
Typically progresses more slowly than meningococcaemia. The rash of RMSF begins on the distal extremities and spreads proximally.
Hyponatraemia, hypoalbuminaemia, and mild hepatitis are common laboratory abnormalities. Serological testing confirms RMSF.
Ehrlichia
Typically progresses more slowly than meningococcaemia. Rash is uncommon, especially in adults.
Serological testing confirms erlichiosis. Inclusion bodies (morulae) may be seen in peripheral blood leukocytes.
Anaplasma
Typically progresses more slowly than meningococcaemia. Rash is uncommon.
Serological testing confirms anaplasmosis. Inclusion bodies (morulae) may be seen in peripheral blood leukocytes.
Infective endocarditis
Bacterial endocarditis infrequently progresses rapidly to septic shock or meningitis, and patients typically have a longer duration of fever prior to presentation. A new or changed heart murmur, septic emboli, immunological sequelae such as glomerulonephritis, and splenomegaly are common in endocarditis and not observed with meningococcal infections.
Echocardiography typically demonstrates a valvular or intracardiac abnormality
Toxic shock syndrome (TSS)
Non-purulent conjunctivitis, pharyngitis, and erythroderma or a scarlatiniform rash that later desquamates are characteristic of TSS. GI complaints, hepatitis, severe muscle pain, elevated serum creatine kinase (CK), and renal abnormalities are more common in TSS than in meningococcal infections. Focal pyogenic infections may be observed in patients with TSS, particularly those caused by staphylococci.
Blood cultures are positive in about half of patients with streptococcal TSS and 5% with staphylococcal TSS.
Enteroviral infection
Rashes are most commonly erythematous and maculopapular but may be petechial. Stomatitis is characteristic of group A Coxsackie viruses.
Cerebrospinal fluid (CSF) from patients with enteroviral meningoencephalitis typically reveals mild lymphocytic pleocytosis, mildly elevated or normal glucose, and normal protein concentration. Enterovirus may be isolated from blood, CSF, stool, throat, or urine. Enteroviral nucleic acid may be detected in CSF.
Epstein-Barr virus
Cervical and generalised adenopathy, hepatosplenomegaly, and hepatitis are common. Severe illness is rare.
EBV infection is diagnosed serologically. Nucleic acid detection may confirm EBV in immunocompromised patients.
CMV
Beyond the neonatal period, a haemorrhagic rash is unusual. Pharyngitis, cervical adenopathy, and hepatosplenomegaly are common. Severe illness, with pneumonitis, chorioretinitis, enteritis, hepatitis, meningoencephalitis, coagulopathy, and pancytopenia, occurs in neonates and immunocompromised patients.
CMV infection is confirmed by serology, viral culture, antigen detection, or nucleic acid amplification.
Parainfluenza
Respiratory symptoms including pharyngitis, rhinitis, and cough are prominent. Rash is uncommon, but petechiae may be present.
Parainfluenza virus infection may be confirmed by viral culture, antigen detection, or nucleic acid amplification.
Respiratory syncytial virus
There may be an on-going community outbreak. Respiratory symptoms, including pharyngitis, rhinitis, and cough, are prominent. Rash is uncommon, but petechiae may be present.
Respiratory syncytial virus infection may be confirmed by viral culture, antigen detection, or nucleic acid amplification.
Influenza
There may be an on-going community outbreak. Respiratory symptoms, including pharyngitis, rhinitis, and cough, are prominent. Rash is uncommon, but petechiae may be present.
Influenza may be confirmed by viral culture, antigen detection, or nucleic acid amplification.
Dengue/yellow fever
There may be a history of travel to an endemic area 1 to 12 days prior to symptoms. Hepatitis and jaundice are more common in viral haemorrhagic fevers than in meningococcal infections.
Serological testing confirms a viral haemorrhagic fever.
Idiopathic thrombocytopenic purpura (ITP)
Typically, lack of fever or other signs of infection.
Bone marrow aspirates or biopsy, assays for the presence of antiplatelet antibodies or evaluation for other autoimmune disorders, and tests for coagulation factor deficiencies confirm ITP.
Henoch-Schonlein's purpura
Palpable purpuric rash, most commonly on the lower extremities; abdominal pain and vomiting; joint pain; and swelling and oedema of the distal extremities, scalp, and scrotum.
Haematuria and proteinuria are common. Skin biopsy demonstrates a leukocytoclastic vasculitis.
Thrombotic thrombocytopenic purpura (TTP)
Fever less common than in meningococcaemia.
Microangiopathic haemolytic anaemia, thrombocytopenia (platelets <50 x 10^9/L), elevated serum lactate dehydrogenase (LDH) concentration, and hyperbilirubinaemia are typical.
Aplastic/myelodysplastic syndromes
Fever less common than in meningococcaemia but may be present in patients with secondary infections. Most patients have physical and laboratory findings suggestive of their primary disorder, such as bleeding from mucosal sites and pancytopenia.
Typical laboratory findings of bone marrow failure syndromes include pancytopenia and evidence of abnormal haematopoiesis on bone marrow exam.
Bone marrow infiltration by malignancy
Most patients have physical and laboratory findings suggestive of their primary disorder, such as weight loss, splenomegaly, adenopathy, and pancytopenia.
Examination of peripheral blood and/or bone marrow confirms malignancy.

Meniscal tear

Anterior cruciate ligament tear
Subluxation on twisting, turning, or pivoting; some patients can feel this coming on, while other patients are not able to feel it and may experience frequent falls due to their injury.Positive Lachman's test, anterior drawer test, and pivot shift test on physical examination.
MRI scan reveals ruptured anterior cruciate ligament (ACL) and disruption of ACL fibres, usually associated with bone bruising in acute setting.
Medial collateral ligament sprain
True dynamic instability is rare, unless it is a complete tear or associated with other injuries. Tenderness over medial collateral ligament (MCL) course/insertion may be present. MCL stress testing reveals laxity and/or pain.
MRI scan reveals fluid around or injury to MCL and differentiates between an isolated MCL injury and one combined with a meniscal tear.Subsequent x-rays may reveal calcification along previously injured MCL (Pellegrini-Stieda's disease).
Posterior cruciate ligament sprain
Patient is often able to continue activity but notes that the knee does not feel right.Instability may be more subtle, with knee effusion typically small and less noticeable. In addition, the posterior drawer test is positive.
MRI scan reveals disrupted posterior cruciate ligament and intact menisci.
Lateral collateral ligament sprain
Local swelling is common, but significant effusion is rare. There is tenderness over the lateral collateral ligament (LCL) and/or bony insertion.A complete tear often results in a palpable gap. [18]
MRI reveals fluid around or disruption to the LCL and differentiates between an isolated LCL and one combined with a meniscal tear.
Osteochondritis dissecans
A joint condition in which some parts of the joint cartilage and bone lose their blood supply due to an unknown aetiology, and may detach from the joint surface. Adolescents are commonly affected. May present with knee pain and swelling. Catching of the knee can occur, especially during or after sporting activity.
X-ray or MRI scan of the affected knee will reveal the osteochondral lesion. MRI can be of particular use in detecting the early phase of the condition.
Osteochondral fracture
Caused by a twisted knee, usually occurring during sporting activity. Presents with knee pain, swelling, and catching. The osteochondral fragment is detached. The medial femoral condyle is frequently involved.
X-rays or other advanced imaging including CT scan or MRI may demonstrate the osteochondral fragment.
Medial synovial plica syndrome
The synovial fold on the medial side of the knee is called the medial plica. This stucture is sometimes exposed to direct injury or impingement between the patella and medial femoral condyle. It may also be injured in overuse syndromes. The injured medial plica causes irritation and inflammation of the knee presenting with knee swelling and pain usually in a medial distribution, although can involve the superior or lateral aspect of the knee.
MRI scan usually confirms the diagnosis. However, arthroscopy may be necessary.

Menopause

Pregnancy
Amenorrhoea with breast tenderness, fatigue, nausea, and an enlarging abdomen may be pregnancy.
An hCG level (in urine samples) of <5 IU/L (<5 mIU/mL) is considered negative for pregnancy, and anything >25 IU/L (>25 mIU/mL) is considered positive for pregnancy. Every woman's level of hCG can rise differently. It is not necessarily the level that matters but rather the change in the level.
Hyperthyroidism
A woman with hyperthyroidism may have menstrual irregularity but may also have tachycardia, tremor, hair loss, anorexia, and weight loss.
TSH levels may be suppressed (<0.01 mIU/mL).
Hypothyroidism
With hypothyroidism, a woman may experience heavy bleeding and irregular periods. Other symptoms are fatigue, hair loss, dry skin, constipation, and weight gain, which may mimic menopausal symptoms.
TSH levels may be elevated (>10 mIU/mL).
Anorexia
A patient with onset of anorexia later in life may also have amenorrhoea, vaginal dryness, and sleep disturbance but usually will also be underweight and may have electrolyte disturbance, anaemia, and bradycardia or other cardiac arrhythmias. Do not experience hot flushes. It is normally possible to differentiate an eating disorder from premature menopause by taking a careful history of eating habits and measuring FSH.
FSH levels will be low to normal (c.f., high in menopause). There may be electrolyte disturbance, anaemia, and bradycardia in severe cases of anorexia nervosa.
Adverse effects of medications such as nitrates, niacin, raloxifene, or tamoxifen
Tamoxifen, a selective oestrogen receptor modifier previously used in patients with breast cancer to prevent recurrence, is notorious for causing hot flushes and vaginal dryness. Raloxifene, also a selective oestrogen receptor modifier, is used for preservation of bone density in post-menopausal women and also results in hot flushes. Niacin, which is prescribed to raise high-density lipoprotein cholesterol levels, also can cause hot flushes. It is important to take a careful medication history, including herbals, which may affect pharmacokinetics of another medication
Consider a trial of withholding the pertinent therapy if possible, to see if the hot flushes are primarily medication-induced.

Mesothelioma

Benign reactive mesothelial hyperplasia
Can be caused by several different processes; therefore, a history of infection, pulmonary infarcts, drug reactions, collagen vascular diseases, trauma, or surgery may be present. [24]
Pleural biopsy is necessary to distinguish benign mesothelial hyperplasia from malignant pleural mesothelioma; invasion of underlying tissues favours mesothelioma. [24]
Benign asbestos-related pleural reactions
Exposure to asbestos can cause several benign pleural reactions, including pleural effusion, pleural plaques, diffuse pleural fibrosis, and rounded atelectasis. [6] Differentiating these processes from malignant pleural mesothelioma can be difficult.
Pleural plaques are frequently documented on plain chest x-ray, but CT is more sensitive for their detection. Slow progression of plaques is typical. The presence of plaques is associated with a greater risk of mesothelioma, but this is thought to be related to greater exposure or retained body burden, not malignant degeneration. [25]Findings on chest CT scan (serial studies usually necessary) suggesting a malignant process include circumferential or nodular pleural thickening, involvement of the mediastinal pleura, or enlarged regional lymph nodes. [18]
Non-small cell lung cancer
Typical features include cough, haemoptysis, chest pain, dyspnoea, and hoarseness (if recurrent laryngeal nerve paralysis).Patients frequently look unwell, are short of breath, with signs of recent weight loss. Finger clubbing and hypertrophic osteoarthropathy may be present.
Chest CT scan shows size, location, and extent of primary tumour; evaluates for hilar and/or mediastinal lymphadenopathy and distant metastases.Sputum cytology shows characteristic malignant cells. Specificity greater than 95%, sensitivity variable between 20% and 70%. More likely to be positive with central lesions compared with peripheral lesions.Flexible bronchoscopy plus biopsy provides pathological confirmation of diagnosis.
Small cell lung cancer
Typical features include cough, haemoptysis, chest pain, dyspnoea, and hoarseness (if recurrent laryngeal nerve paralysis).Patients frequently look unwell and are short of breath with signs of recent weight loss.Finger clubbing and hypertrophic osteoarthropathy may be present but are less common in small cell lung cancer compared with non-small cell lung cancer.Usually, wheezing from underlying COPD or bronchial obstruction, rales due to post-obstructive pneumonia or atelectasis, or diminished breath sounds from bronchial obstruction are present unless early disease.
Chest CT scan shows massive lymphadenopathy and direct mediastinal invasion.Sputum cytology shows characteristic malignant cells. Specificity greater than 95%, sensitivity variable between 20% and 70%. More likely to be positive with central lesions compared with peripheral lesions.Flexible bronchoscopy plus biopsy provides pathological confirmation of diagnosis.
Metastatic cancer
Symptoms will relate to the site of the primary tumour, and there may be general symptoms of pain, weight loss, malaise, cough, dyspnoea, clubbing, and focal wheezing.Physical findings may or may not be present depending on nature and stage of tumour.
Chest CT scan shows one or multiple nodules of variable sizes from diffuse micronodular shadows (miliary) to well-defined masses.Flexible bronchoscopy and biopsy shows characteristic malignant cells.

Metabolic syndrome

Chronic liver disease
Presence of stigmata of chronic liver disease (e.g., spider angioma, telangiectasia, collateral circulation of the abdominal wall around the umbilicus).Other clinical features include jaundice, hepatosplenomegaly, abdominal distension, and ascites.
Liver function tests: elevated ALT and AST.Gamma-GT: may be elevated.Serum albumin and sodium: reduced.Prothrombin time: prolonged.Platelet count: reduced.Bilirubin: may be elevated.
Cushing's syndrome
Signs of hypercortisolism: central obesity, plethoric 'moon face', 'buffalo hump', acne, purple striae.
Serum cortisol (morning and midnight samples): elevated, loss of diurnal rhythm.Urinary cortisol: elevated.Overnight suppression test: no suppression of morning (8 a.m.) cortisol levels after taking 1 mg dexamethasone (11 p.m.) the previous night (48-hour suppression test with 2 mg of dexamethasone is an alternative).Late-night salivary cortisol: elevated.Patients with an abnormal result should undergo a second test, or a serum midnight cortisol or dexamethasone/corticotrophin-releasing hormone test. [56]
Congenital adrenal hyperplasia
Associated with obesity, insulin resistance, and hypertension with additional signs of hyperandrogenism (genital ambiguity in females, precocious puberty in males). Rarely, signs and symptoms of salt loss including hypotension may be present.If undiagnosed and untreated, may progress to a life-threatening adrenal crisis with vomiting, diarrhoea, hypoglycaemia, hypovolaemia, and shock.
17-hydroxyprogesterone levels: elevated. [57]

Metastatic breast cancer

Lung cancer
Haemoptysis may occur.Shortness of breath (SOB) is a more common symptom, often related to a history of smoking.
CXR or chest CT scan frequently demonstrates a single pulmonary lesion, often in the central bronchial region, in people with lung cancer.Multiple lesions on CXR or chest CT scan more likely in people with MBC. [29]Biopsy of the lesion consistent with lung or breast primary.
Osteosarcoma
More likely to present in younger patients.Usually affects weight-bearing bones (e.g., femur), whereas the ribs are a common site for bony metastases in MBC.
A single bone lesion, rather than multiple, on bone scan, with or without PET.Biopsy may be necessary if a single lesion is present, to determine tumour origin.
Breast sarcoma
Much less common than MBC.More likely: to have a history of radiation to the breast; for lesion to develop within the irradiated area; for there to have been a tumour-free-interval of at least 5 years after end of radiotherapy. [30]Unlike radiation-induced breast sarcoma, the risk of breast carcinoma relapse is highest in the first 2 to 3 years after surgery. [31]
Imaging is generally not helpful.Biopsy with pathological evaluation is required.
Brain cancer
No other evidence of metastatic disease.
Brain metastases from MBC often demonstrate ring enhancement on CT and MRI, whereas primary neoplasms of the brain generally do not demonstrate this effect. [32]More likely to present on imaging as a single brain lesion rather than multiple lesions.Brain oedema is common with glioblastoma, a form of primary brain cancer.

Migraine headache in adults

Headache, tension
Frequently co-exists with migraine in the same patient. [72]Tension-type headache is an uncommon reason for patients to seek medical care, unless it is very frequent.More than 90% of patients diagnosed in primary care with tension-type headache in fact have migraine, [73] and 75% of migraineurs have neck pain with attacks.Attacks are generalised throughout the head; often bilateral pressure-like and non-throbbing pain. Often described as feeling like a tight band around the head.No more than one of photophobia, phonophobia, or mild nausea may be seen. Moderate or severe nausea or vomiting excludes the diagnosis.The distinction is best made by taking a careful history and having the patient keep a diagnostic headache diary. [74]
There are no differentiating tests.
Headache, cluster
Cluster headache is more common in men. [75]Attacks last less than 3 hours, and cause restlessness and agitation with autonomic signs or symptoms on the side of the pain. [1]Attacks may occur at exactly the same time of the day or night (so-called 'alarm clock' headaches), especially during rapid eye movement (REM) sleep. [76]By contrast, migraine is more common in women. [75]The distinction is best made by taking a careful history and having the patient keep a diagnostic headache diary. [77] [78] [79]
There are no differentiating tests.
Medication-overuse headache
This headache has a mixed picture of both migraine and tension-type features.Can be globalised and associated with nausea. Requires analgesia at least 2 or 3 days each week, with intake of the drug on at least 10 days per month for at least 3 months.Because they are available without a prescription, over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin, especially aspirin/paracetamol/caffeine combinations, are common causes of medication-overuse headache.
There are no differentiating tests.
Post-traumatic headache
Post-traumatic headaches have no defined features and can mimic most forms of primary headache, including migraine.In a patient with a prior history of migraine, worsening of headache in response to head trauma is considered to be an aggravation of migraine.Diagnosis is made on the basis of the history. Post-traumatic headache is diagnosed only when a new type of headache begins for the first time within 7 days of head or neck injury. [1]
There are no differentiating tests.
Subarachnoid haemorrhage (SAH)
SAH is commonly a severe, sudden-onset headache (often called a 'thunderclap' headache), although up to 50% of patients may have a prodrome of a lower-grade 'sentinel' headache. [80]As with migraine, analgesics or triptans may improve the pain. [81]The physical examination may be normal, although up to 25% of patients have neurological findings. [80]
Plain CT scans can detect the presence of gross blood, but if CT is negative, consider LP in patients with a history strongly suggestive of SAH. Angiography may be needed. [80]
Cerebral neoplasm
While headache is a common symptom in patients with cerebral neoplasms, it has no consistent characteristics and rarely occurs in the absence of other suspicious historical or examination features.Suspicion is increased in patients with a progressive pattern of headache worsening in conjunction with the development of new neurological signs or symptoms.Papilloedema on fundoscopic examination should prompt consideration of a neoplastic or other cause of high CSF pressure. [82]
CT or MRI scans may identify space-occupying lesions.
Low-pressure headache
Low CSF pressure headache is often worsened with standing and improved with lying down. [83]It can result from a spontaneous or iatrogenic dural tear: for example, following craniotomy or epidural analgesia.
The diagnosis of low-pressure headache can be very difficult if the dural tear occurred spontaneously. LP may show a low opening pressure, and MRI scans of the brain with gadolinium may demonstrate pachymeningeal enhancement. [69] [70] [71] Spinal myelogram with CT imaging may demonstrate contrast extravasation. [84]
High-pressure headache (idiopathic intracranial hypertension)
Historical and physical examination features suggestive of high-pressure headaches include visual disturbances and tinnitus.High CSF pressure can result from intracranial pathology, such as cerebral neoplasms, or from idiopathic intracranial hypertension (IIH).IIH is most common in obese women of childbearing age and is also associated with the use of certain antibiotics and oral contraceptives. [85]
LP may show a high opening pressure, but must not be done in the presence of papilloedema until an imaging study has been performed.
Systemic or CNS infection
Headache is a common feature of both systemic nervous system and CNS infections, and has no consistent clinical characteristics.The diagnosis is straightforward in the presence of a high fever or altered consciousness. Indolent CNS infections, however, can be more difficult to diagnose.Suspicion for these disorders should be increased in patients with systemic disorders (especially immune compromise) that predispose to infection with Toxoplasma gondii, Cryptococcus, or cytomegalovirus. [86] [87] [88] [89]
Culture and microscopy of CSF and samples from other potential sites of infection may identify the infecting micro-organism.
Temporal (giant cell) arteritis
Temporal arteritis should be considered in patients over the age of 50 years with new-onset or worsening headache.It is most common in people of northern European descent. [90]If untreated, permanent visual loss can occur.The headache has no characteristic features, but it commonly improves or disappears within 3 days of beginning high-dose corticosteroid treatment. [1]Historical features include a history of jaw claudication, muscle pain, and a tender temporal artery. [90]
ESR is raised in more than 90% of patients, to a median value of 65 mm/hour; biopsy of temporal artery shows typical inflammatory infiltrate. [68]
Arterial dissection
Headache and/or neck pain occurs in more than 50% of cases of cervical artery dissection. This is the most frequent initial symptom (33% to 86% of cases) and can occasionally be the only symptom.The headache has no consistent features, and can mimic primary headache disorders or present as a sudden, severe 'thunderclap' headache. [91]Headache is usually found on the same side as the dissection and can occur with Horner's syndrome or tinnitus. [92]
Angiography may demonstrate the lesion.
Cerebral venous thrombosis (CVT)
Headache is the most common symptom (80% to 90% of cases) and the most common initial symptom in CVT.The headache has no specific characteristics, can mimic any of the primary headache disorders, and can be a sudden, severe-onset 'thunderclap' headache. [93]In 90% of patients, CVT is associated with focal neurological signs and evidence of idiopathic intracranial hypertension. [93]
Neuroimaging (magnetic resonance venogram) is generally necessary for definitive diagnosis. [63]
Ischaemic stroke
Headache can be a symptom of ischaemic stroke. Migraine, particularly with aura, is an independent risk factor for ischaemic stroke, with highest risk in women aged under 45 years. [94] [95]Neurological deficit in stroke or TIA is usually maximal at onset and lasts longer than an hour. [96]Migraine aura can be confused with ischaemic stroke or TIA, but typically develops gradually, consists of positive and negative symptoms with no relevant imaging abnormalities, and is fully reversible. [97]
CT scans or MRI scans may detect ischaemic lesions.

Miliaria

Fox-Fordyce disease (apocrine miliaria)
Intensely pruritic papules in adult women localised to the axillae, groin, pubic region, and areola.No relationship to heavy sweating, heat, humidity, occlusion, sunburn, or febrile illness and no associated anhidrosis.Papules are folliculocentric and flesh-coloured to brown with no erythema or vesiculation. [26]
Diagnosis is primarily clinical.Biopsy demonstrates follicular plugging with no involvement of the eccrine duct. [26]
Primary varicella infection
Eruption of macules followed by vesicles on an inflammatory base, mainly on the trunk, face, and oral mucosa that go through stages, unlike miliaria. Lesions are in all stages of development (macules, papules, vesicle, ulcers, and crusts) simultaneously. [27]Eruption is highly contagious, unlike miliaria, and often occurs in epidemics among young nonimmunised or previously unexposed children.Eruption has no relationship to heat, humidity, or occlusive clothing.
Diagnosis is primarily clinical.Tzanck smear shows multinucleated giant cells in a herpetic viral infection. These would be absent in miliaria.Positive viral direct immunofluorescence (DIF)/viral culture or skin biopsy.
Disseminated varicella-zoster infection
Eruption of vesicles, similar to primary varicella infection, often in immunocompromised, older, or debilitated patients.Often dermatomal distribution with many non-dermatomal vesicles.Patients are often systemically ill and may have involvement of the lungs, liver, or CNS. [28]
Diagnosis is primarily clinical.Tzanck smear shows multi-nucleated giant cells in a herpetic viral infection. These would be absent in miliaria.Positive viral DIF/viral culture or skin biopsy.
Acne vulgaris
Folliculocentric papules, pustules, and comedones that can involve the chest and back only but more often also involve the face. Lesions of miliaria are always non-folliculocentric and lack comedones.
Diagnosis is primarily clinical.Biopsy demonstrates folliculocentric acute and chronic inflammation.
Folliculitis
Folliculocentric pustules that may be associated with occlusive clothing and heat/humidity. Lesions of miliaria are always non-folliculocentric.
Diagnosis is primarily clinical.Biopsy demonstrates folliculocentric acute inflammation.
Steatocystoma multiplex
Multiple 2- to 6-mm yellowish cystic papules on the upper trunk, upper arms, and axillae that contain a yellow oily material.Unrelated to heat, humidity, or occlusion and often familial (demonstrating an autosomal-dominant mode of inheritance) though sporadic cases are common. [29]
Diagnosis is primarily clinical.Biopsy demonstrates a cyst lined by epithelium with a crenulated inner lining and sebaceous lobules in the outer wall.
Transient acantholytic dermatosis (Grover's disease)
Eruption of pruritic non-folliculocentric erythematous papulovesicles on the trunk most commonly in adult males.Although related to heat and sweating, Grover's disease tends to be much more persistent, never has a clear vesicular appearance like miliaria crystallina, and is never associated with anhidrosis. [30]
Can be difficult to distinguish from miliaria rubra.Biopsy demonstrates epidermal acantholysis with dyskeratosis, corps ronds, and corps grains.
Erythema toxicum neonatorum
Common eruption in healthy full-term newborns in the 2nd or 3rd day of life. Diffuse eruption of folliculocentric pustules on an erythematous base involving the face, trunk, and proximal extremities. [31] Miliaria, in contrast, rarely involves the face and is never folliculocentric.
Diagnosis is primarily clinical.Smear from a pustule stained with Giemsa demonstrating eosinophils is diagnostic.Biopsy demonstrates subcorneal pustules in the vicinity of a hair follicle, filled with eosinophils.
Transient neonatal pustular melanosis
Eruption of 1 to 3 mm non-folliculocentric flaccid fragile pustules in newborns that resolve with hyperpigmentation.Most commonly occurs on the chin, neck, forehead, back, and buttocks and most common in dark-skinned infants. [31]
Diagnosis is primarily clinical. Smear from a pustule stained with Giemsa demonstrating mostly neutrophils is diagnostic.Biopsy demonstrates an intra- or sub-corneal collection of neutrophils.
Bullous staphylococcal impetigo
Eruption of bullae, most commonly in newborn infants, on any body surface. At first, constitutional symptoms are absent. However, eventually fever or a sub-normal temperature may develop.In adults, the eruption commonly involves the axillae, groin, or hands with large fragile bullae that rupture to weepy or crusted lesions. [32]
Gram stain and bacterial culture demonstrating Staphylococcus aureus are diagnostic.
Cutaneous candidiasis
Eruption of red moist patches surrounded by a thin fringe of epidermis ('collarette' scale) with associated surrounding satellite erythematous papules and pustules. Occurs most frequently between folds in the groin, genitals, upper axillae and, in infants, in folds in the nappy area.In the newborn period can occur as a congenital eruption of erythematous macules that progress to pustules that rupture and heal with desquamation. The eruption is often associated with premature rupture of membranes and Candida albicans infection of the birth canal. [33] Unlike congenital miliaria crystallina, the lesions are pustules and not clear vesicles.
Potassium hydroxide (KOH) preparation demonstrating budding yeast and pseudohyphae are diagnostic.Can also confirm with fungal culture demonstrating growth of C albicans.
Herpes simplex
In most cases, there is a high fever above 38°C (100.4°F).Vesicles are small and oval, on an erythematous base and grouped together.
A Tzanck smear of vesicle fluid shows multi-nucleated giant cells.View imageA direct fluorescent antigen test for herpes simplex virus can also be done.

Minimal change disease

Acute glomerulonephritis
Oedema associated with haematuria and hypertension.
Low complement C3; elevated creatinine; decreased GFR; wet lungs on chest x-ray. View image
Focal segmental glomerulosclerosis
Can be either primary (idiopathic) or secondary to another condition (e.g., sickle cell disease, leukemia, renal scarring, or hypoplasia).Hypertension may be present; otherwise, physical examination is non-specific.
Microscopic haematuria.Renal biopsy: focal and segmental sclerosis of the glomeruli.
Congestive heart failure
Patients can present with shortness of breath.Cardiac murmur, cardiomegaly, and hepatomegaly may be present on physical examination.
Abnormal ECG and echocardiogram findings; absence of significant proteinuria on urinalysis.
Kwashiorkor (severe childhood malnutrition)
Patients present with a swollen or a pot belly, alternating bands of pale and dark hair (flag sign), and weight loss.Common skin symptoms include dermatitis and depigmented skin.Most common cause of oedema associated with hypoalbuminaemia in the developing world; rare in US.
Urinalysis: absence of proteinuria.Normal lipid profile.
Cirrhosis
Patients present with hepatomegaly in early stages. Ascites with abdominal venous engorgement and jaundice are common signs.
Abnormal liver enzymes; elevated bilirubin; abnormal coagulation profile with bleeding tendency; positive tests for aetiology (e.g., hepatitis B or C); absence of heavy proteinuria on urinalysis.
Protein-losing enteropathy
GI signs of malabsorption: diarrhoea, steatorrhoea, and/or blood in the stool.
Stool sample: positive for occult blood and fat.Plasma albumin markedly reduced.

Miscarriage

Ectopic pregnancy/heterotopic pregnancy
Atypical symptoms that can be missed include iliac fossa or suprapubic pain, unexplained pallor, tachycardia, or syncope.Positive findings on examination are adnexal tenderness or suggestion of haemoperitoneum.An early intra-uterine pregnancy may co-exist with an ectopic pregnancy.
Trans-vaginal ultrasound scan is diagnostic, depending on the site of the extra-uterine pregnancy and the index of suspicion.Serial measurements of serum beta hCG and a single measure of progesterone may help distinguish between early viable, poor prognosis or ectopic gestation. [62]Scan reveals an empty uterine cavity, a complex or cystic adnexal mass with or without free fluid in the pouch of Douglas.If in doubt, laparoscopy can confirm the diagnosis and will show a distended, reddish fallopian tube.
Hydatidiform mole
Uterine size is much larger than expected for gestational age.Pregnancy symptoms are marked.Very rarely, the patient might have passed some molar, grape-like tissue.
Trans-vaginal ultrasound will reveal the classic snow storm appearance.
Partial hydatidiform mole
Uterine size is much larger than expected for gestational age.Pregnancy symptoms are marked.
Ultrasound may reveal a fetus, with an extensive but unusual-looking placenta.
Cystitis
Suprapubic pain with dysuria and fever.Some patients present with haematuria.
Urine microscopy and culture confirms the diagnosis.
Pregnancy co-existing with a bleeding cervical polyp
May be suspected from appearances of the ecto-cervix on speculum examination.
Confirmed after an ultrasound scan, or by spontaneous avulsion of the polyp.

Mitral regurgitation

Acute coronary syndrome (ACS)
There maybe a history of angina or cardiovascular disease, relief of symptoms with rest or nitrates and risk factors such as family history, smoking, DM, and hyperlipidaemia.The patient with ACS typically presents with central crushing chest pain lasting >20 minutes, often associated with nausea, sweatiness, dyspnoea, and palpitations.
ECG shows ST segment elevation (in ACS with ST elevation) or depression (in ACS without ST elevation), tall or inverted T waves, or new left bundle branch block. Cardiac enzymes are raised.
Infective endocarditis
Typically presents with a new murmur, or change in the nature of an existing one, with fever, anaemia, splenomegaly or clubbing.
Blood cultures are positive in infective endocarditis.A CBC may show anaemia, raised neutrophils, and raised ESR or C-reactive protein.Echo shows vegetations if larger than 2 mm, giving a cause for a new murmur.
Mitral stenosis
Presents with dyspnoea, fatigue, palpitations, and chest pain.Distinguishing features are a malar flush, a low volume pulse, a tapping and undisplaced apex beat, loud S1 with an opening snap.The murmur is a rumbling mid-diastolic one, which can be distinguished from the Austin Flint murmur by the absence of the opening snap and loud S1.
CXR: mitral stenosis may show pulmonary oedema, but other features include enlarged left atrium and mitral valve calcification.ECG: patients with mitral stenosis can present with atrial fibrillation. RVH may be present too.Echo is diagnostic for mitral stenosis.
Aortic stenosis
Presentation includes dyspnoea, dizziness, fainting, and congestive cardiac failure.Characteristic signs are a slow rising pulse, heaving but undisplaced apex beat, left ventricular heave, and an ejection systolic murmur that radiates toward the carotids and can have an ejection click.
CXR: aortic stenosis may show LVH, but other features include a calcified aortic valve.ECG: aortic stenosis may show P mitrale, LVH with strain pattern, left bundle branch block, or complete AV block.Echo is diagnostic for aortic stenosis.
Aortic or pulmonic valve disease
Aortic or pulmonic ejection clicks best heard to the right and left of the upper sternum, respectively. Click timing not affected by dynamic manoeuvres.
Echo is diagnostic for bicuspid aortic valve and pulmonic valvular disease.
Atrial myxoma
May have symptoms of weight loss, fever, and malaise. Exam may reveal a diastolic tumour plop or diastolic murmur.
Heterogeneous masses may be sessile, typically in left atrium. Transoesophageal echo may yield more detail than transthoracic echo. Laboratory evaluation may reveal leukocytosis.

Mitral stenosis

Left atrial myxoma
This left atrial tumour may obstruct the mitral orifice and mimic the signs and symptoms of mitral stenosis.
Echocardiography clearly shows a mass lesion.
Unexplained atrial fibrillation
At rapid heart rates the signs of mitral stenosis may be difficult to discern.
Echocardiography excludes mitral stenosis.

Mitral valve prolapse

Aortic valve disease
Aortic ejection clicks occur earlier in systole than in MVP, best heard to the right of the upper sternum. Click timing not affected by dynamic manoeuvres.
Echocardiogram is diagnostic for bicuspid aortic valve disease as there is a characteristic opening motion of the aortic valve in this condition.
Pulmonic valve disease
Pulmonic ejection clicks occur earlier in systole than in MVP, best heard to the left of the upper sternum. Click timing not affected by dynamic manoeuvres.
Echocardiogram is diagnostic for pulmonic valvular disease as abnormal motion or Doppler findings associated with this valve are evident.
Atrial myxoma
May have symptoms of weight loss, fever, malaise. Examination may reveal a diastolic tumour plop or diastolic murmur similar to mitral stenosis.
Heterogeneous masses, may be sessile, typically in left atrium. Transoesophageal echocardiogram may yield more detail than transthoracic echocardiogram. Laboratory evaluation may reveal leukocytosis.
Ischaemia-related mitral regurgitation (MR)
History reveals previous MI. Examination features are similar to MVP-related regurgitant murmurs. May be late systolic or holosystolic, which can mimic severe MVP-related MR. Absence of click.
ECG reveals previous infarction. Echocardiogram findings may delineate papillary muscle and left ventricular akinesis or dyskinesis. The posterior mitral valve leaflet shows restricted motion as compared with the excess motion seen in MVP.
Rheumatic heart disease-related MR
History of group A streptococcal pharyngitis followed by migratory large-joint arthritis, fever, rash, and subcutaneous nodules. Rheumatic heart disease typically follows 1-2 decades later. Examination features are similar to MVP-related regurgitant murmurs. Usually holosytolic, which can mimic severe MVP-related MR. Absence of click.
ECG may show heart block. Echocardiogram is diagnostic with evidence of restricted motion of both leaflets. A degree of stenosis of the mitral valve with doming of the valve as it opens commonly accompanies the regurgitation.
Infective endocarditis affecting mitral valve
Fever, chills, sweats, weight loss, Osler nodes, subungual haemorrhages, Janeway lesions, Roth spots, petechiae.
Vegetations on echocardiography, typically on the atrial side of the valve. Transoesophageal echocardiogram may be more sensitive than transthoracic echocardiogram. Leukocytosis, anaemia, elevated ESR, microscopic haematuria may be seen.
Tricuspid valve prolapse
While tricuspid prolapse may also produce a mid-systolic click sound, it is best heard at the lower left sternal border, or occasionally on the lower right parasternal area. Timing between the S1 and a tricuspid click often increases after inspiration or other manoeuvres that increase right ventricular return.
Echocardiogram is diagnostic but tricuspid valve prolapse and MVP frequently co-exist, whereas isolated tricuspid valve prolapse is rare.

Molar pregnancies

Spontaneous abortion
Risk factors include older parental age, bacterial vaginosis, and thrombophilias.Pregnancy loss in the first trimester is 18 times greater in patients who bleed moderately to severely.Cramp-like discomfort may signify the process of expulsion of the fetus.
Ultrasound findings of a complete mole are characteristically different from spontaneous abortion. A partial mole may contain a fetal pole or fetus, usually without cardiac activity, and may be more difficult to discriminate from a missed abortion.Inspection of evacuated tissue for hydropic villi, and chromosome testing of evacuated tissue may be confirmatory.
Multiple gestation
Uterus is larger than expected for dates, and there is elevated serum beta hCG with corresponding symptoms of nausea and emesis, but it is rare for molar pregnancies to be associated with multiple gestation.
Ultrasound with uterine enlargement greater than expected for gestational age and multiple fetuses.
Pelvic tumour
May present with an enlarged uterus and painless bleeding of uterine and adnexal masses.The theca lutein cysts of molar pregnancies are typically a painful condition.Nausea, emesis, and hyperthyroidism are not typically seen in pelvic malignancies.
Serum beta hCG is rarely elevated with pelvic tumours (with the notable exception of choriocarcinoma).Ultrasound of the pelvis demonstrates uterine mass or abnormal adnexal organs.Pelvic CT generally is diagnostic.Pathology of the products of dilation and suction evacuation may confirm tumour histology.

Molluscum contagiosum

Warts
All warts have abnormal skin markings or dermatoglyphics. Verrucous papules and plaques typify most warts, the sole being the most common location. Some warts are filiform coming to a point, and on the genitalia condyloma, are usually flat plaques.
Paring warts reveals pinpoint bleeding. Biopsy specimens demonstrate verrucous hyperkeratotic skin lesions as opposed to Henderson-Patterson bodies seen in molluscum.Immunoperoxidase staining or in situ PCR can be done to identify human papillomavirus subtypes, which are the molecular confirmation techniques for warts.
Deep fungal infection (Cryptococcosis and Penicillium marneffei)
Patients with Cryptococcosis and Penicillium marneffei infection are very ill, usually immunosuppressed, with fever and systemic symptoms including CNS changes.
Fungal smears, cultures and latex agglutinin tests from lesions, spinal taps and blood will demonstrate fungal elements. A skin biopsy stained with fungal stains will demonstrate spores.
Milia
While these lesions are small papules with central orifices, they tend to be smaller than and not as pearly as molluscum. Milia typically occur over the cheeks, whereas molluscum is seen in the axilla or groin more commonly.
Biopsy can differentiate these two, but as both conditions are benign, it is rarely needed.

Monoclonal gammopathy of undetermined significance

Multiple myeloma or smoldering myeloma
Common symptoms: weakness and fatigue, bone pain, recurrent infections, confusion and altered mental status related to metabolic complications, and numbness and tingling related to neuropathy or compressive symptoms. These are vague and non-specific signs.
By definition, the diagnosis of MGUS requires the absence of anaemia, hypercalcaemia, renal failure, and lytic bone lesions related to the plasma-cell proliferative disorder.Serum monoclonal (M) -protein concentration >30 g/L (3 g/dL) by definition indicates multiple myeloma or a related malignancy, but some of these patients have smoldering/asymptomatic myeloma and remain stable during long-term follow-up. [22]Only patients in whom these clinical findings of end-organ damage are felt to be clearly related to the plasma-cell disorder are considered to have multiple myeloma.Although the predictive value may not be high, higher concentrations of serum M proteins are associated with a greater likelihood of malignancy. [23]
Amyloidosis
Significant degrees of proteinuria, hepatomegaly, or cardiomyopathy.
Sural nerve or tissue biopsy is positive with Congo red staining.
Waldenstrom's macroglobulinaemia
Symptoms related to hyperviscosity syndrome, hepatomegaly, splenomegaly, lymphadenopathy, anorexia, and fatigue.
Possible abnormal FBC.Serum IgM: >30 g/L (3 g/dL).Bone marrow biopsy: >10% of lymphoplasmacytic cells.
Chronic lymphocytic leukemia
Lymphadenopathy and splenomegaly. Anaemia is less common but a strong diagnostic factor and may cause lethargy and shortness of breath.
Elevated WBC with absolute lymphocytosis >5 X 10\u06f8/L (5000/microliter); anaemia and thrombocytopenia are less common.Flow cytometry positive for CD5, CD19, and CD23 confirms diagnosis.
Non-Hodgkin's lymphoma
Constitutional symptoms, such as night sweats, fevers, and weight loss, are common. Lymphadenopathy and splenomegaly may also be present.
FBC with differential may show thrombocytopenia or pancytopenia.Bone marrow or lymph node biopsy may be positive for lymphoma.
Peripheral neuropathy
In chronic inflammatory demyelinating polyradiculoneuropathy, weakness may be prominent. Features of the underlying cause (e.g., indications of infection or malignancy) may be present.
Nerve conduction studies and needle EMG help to confirm clinical diagnosis and determine whether the neuropathy is primarily axonal or demyelinating. If electrodiagnostic study reveals a demyelinating polyneuropathy, specific aetiologies should be considered.

Mononeuritis multiplex

Diabetic lumbosacral radiculoplexus neuropathy
Patients may not have been diagnosed with diabetes, and may present with weight loss.Patients have prominent lower extremity proximal pain, with asymmetrical lower extremity proximal weakness more than distal weakness.Weakness usually involves both thigh adductors and knee extensors.Sensory loss is not as prominent as motor weakness, but some evidence of distal length-dependent sensory loss is also present.
Electrodiagnostic testing shows evidence of a lumbosacral radiculoplexus neuropathy. Nerve root involvement can often be confirmed and is a typical and distinctive finding.Serum glucose may or may not be abnormal at presentation as patients often have lost weight as part of the prodrome and the course of the disorder. HgA1C may be elevated in these cases.
Multiple compression/entrapment mononeuropathies
Usually presentation involves median neuropathy at the wrist (i.e., carpal tunnel syndrome), ulnar mononeuropathy at the elbow, and lateral femoral cutaneous neuropathy (i.e., meralgia paraesthetica).Patients do not have symptoms or signs involving other organ systems to suggest systemic vasculitis.Bilateral median neuropathy at the wrist may occur without suspicion for mononeuritis multiplex (MNM).Bilateral, painful peroneal mononeuropathies or a unilateral sciatic neuropathy are likely to represent a vasculitic process.
Electrophysiological testing helps to show the severity of the entrapment mononeuropathies and the location of the entrapment, and suggests a diagnosis.There is often demyelination of the nerve at the site of entrapment, which is not consistent with a typical vasculitic MNM. [1]
Hereditary neuropathy with liability to pressure palsies
Presents with episodic, painless, recurrent mononeuropathies from minimal compression (e.g., after 20 minutes of kneeling, a peroneal mononeuropathy may develop with pronounced foot drop and sensory deficit in the dorsal foot and lateral calf).Patients do not have symptoms or signs involving other organ systems to suggest a systemic vasculitis.Affected nerves often recover within a few days or weeks, consistent with a demyelinating lesion of the nerve, differentiating from longer recovery periods associated with axonal neuropathy secondary to vasculitis or other causes.
Electrophysiological testing shows generalised, mildly prolonged distal motor latencies and typically conduction block at the site of entrapment mononeuropathy.Positive genetic testing for PMP22 deletion confirms the diagnosis. [1]
Multifocal sensorimotor demyelinating neuropathy (Lewis-Sumner syndrome)
Typically presents with numbness and paraesthesia within the territories of single nerves of the upper extremities, resulting in progressive weakness and atrophy.Patients do not have symptoms or signs involving other organ systems to suggest a systemic vasculitis.The chronic, slow progressive course and upper extremity involvement differentiate this disorder from a typical vasculitic MNM.
Electrodiagnostical testing shows motor and sensory conduction block in the affected nerves, often even if the deficits have been present for years.Peripheral nerve demyelination is not consistent with typical vasculitic MNM.
Multifocal motor neuropathy with conduction block
Presents with pure motor findings, with muscle weakness, fasciculations, and decreased reflexes in the territory of the involved nerves.Weakness is asymmetrical and upper extremity weakness predominates, typically without pain.Patients do not have symptoms or signs involving other organ systems to suggest a systemic vasculitis.The lack of sensory findings and upper extremity predominance differentiates from a typical vasculitic MNM.
Electrodiagnostical testing shows motor conduction block in the affected nerves.Peripheral nerve demyelination is not consistent with typical vasculitic MNM.
Multifocal motor neuropathy without conduction block
Patient presentation is similar to patients with multifocal motor neuropathy with conduction block.
Electrodiagnostical testing shows motor neuropathy without evidence of involvement of sensory nerves. Conduction block is not found, distinguishing this from multifocal motor neuropathy with conduction block.
Guillain-Barre syndrome
May present asymmetrically, but deficits are usually not within the distribution of specific nerves.Patients do not have symptoms or signs involving other organ systems that would suggest systemic vasculitis.
Electrodiagnostic studies may show early absence of F-waves or evidence of peripheral nerve demyelination.
Chronic inflammatory demyelinating polyneuropathy
Differentiated from vasculitic MNM by the fact that motor and sensory symptoms typically develop insidiously over weeks to months and are not within the distribution of specific peripheral nerves. Patients do not have symptoms involving other organ systems to suggest systemic vasculitis.
Electrodiagnostical testing shows a demyelinating acquired peripheral polyneuropathy.Peripheral nerve demyelination is not consistent with a typical vasculitic MNM.

Motion sickness

Migraine attack
May be indistinguishable clinically.Presence of migraine may cause motion sickness to develop more rapidly in the appropriate setting.Migraine may be accompanied by aura and usually persists for hours beyond the motion exposure.
There are no laboratory tests for differential diagnosis. Head imaging may exclude alternative diagnoses.
Food poisoning
Travel history or ingestion of high-risk foods may suggest food poisoning.The acute phase of food poisoning is less likely to be associated closely with motion provocation and may persist after motion.A combination of nausea and diarrhoea with severe stomach cramps is more likely with food poisoning.
May identify aetiological agents from faecal samples.
Acute vestibular disorder
Dizziness (in the form of rotatory vertigo) with nystagmus and gait ataxia will be dominant features that accompany nausea and vomiting.
Investigations such as audiology or MRI of the head may exclude specific pathologies.

MRSA

Insect or spider bite
Spider bites may show puncture marks or be witnessed.Less likely to have central ulceration with surrounding erythema or pain.More likely to respond to penicillins or cephalosporins.Risk factors for MRSA infection may not be present.
Culture and antibiotic susceptibilities of the wound or abscess negative for MRSA.Gram stain is appropriate for initial classification of the possible pathogen.
Cellulitis
Cellulitis is less likely to present as erythematous lesions or pustules, in single or multiple forms. It is less likely to be mistaken for an insect bite or folliculitis.Risk factors for MRSA infection may not be present.
Culture and antibiotic susceptibilities of exudate negative for MRSA.
Folliculitis
Patients often present with single or multiple skin lesions or pustules, which may be difficult to differentiate from community-acquired MRSA infection.Risk factors for MRSA infection may not be present.
Culture and antibiotic susceptibilities of drainage negative for MRSA.
Pneumonia, not due to MRSA
Presentation may be similar to that of patients with MRSA pneumonia.Patients present with fever, chills, cough, and shortness of breath, and are often severely ill.Risk factors for MRSA infection may not be present.
Blood culture, sputum culture negative for MRSA.MRSA pneumonia may have multi-lobar infiltrates that cavitate on CXR.
Bacteraemia, not due to MRSA
Presentation may be similar to that of patients with MRSA bacteraemia.Risk factors for MRSA infection may not be present.
Blood culture negative for MRSA.
Urinary tract infections, not due to MRSA infection
Patients may present with painful urination, haematuria, fever, altered mental status, chills, or urinary retention.Presentation may be similar to that of patients with MRSA UTI.Risk factors for MRSA infection may not be present.
Urine culture negative for MRSA.
Infective endocarditis, not due to MRSA infection
Presentation may be similar to patients with MRSA endocarditis.Risk factors for MRSA infection may not be present.
Blood culture negative for MRSA.
Joint infections, not due to MRSA infection
Presentation may be similar to that of patients with MRSA joint infection.Risk factors for MRSA infection may not be present.
Joint aspirate culture negative for MRSA.

Mucormycosis

Aspergillosis
No differentiating signs or symptoms especially in pulmonary disease, except presence of accompanying sinus disease, makes aspergillosis less likely.
Histopathology in aspergillosis demonstrates narrow (2.5-4.5 micrometres) septate hyphae, branching at an acute angle of 45°.Positive serum galactomannan assay may favour the diagnosis of aspergillosis.
Bacterial sinusitis
Clinically indistinguishable from mucormycosis in the initial stages, but typically responds to antibacterial therapy and lacks necrotic eschar.
Sinus puncture with culture may be indicated when standard antibiotics have failed, however, this is considered controversial.
Bacterial peri-orbital cellulitis
No differentiating signs and symptoms in the initial stages, but more commonly lacks risk factors, has history of trauma, and responds to antibacterial therapy.
Blood/eye swab cultures: positive for bacterial culture.
Sinus lymphomas
B-cell or T-cell lymphomas may have presence of lymphadenopathy elsewhere in the body.
Histopathology of biopsy is crucial and demonstrates atypical cells consistent with lymphoma.
Wegener's granulomatosis
May have renal failure and systemic manifestations of vasculitis in addition to sinus symptoms similar to mucormycosis.
Blood test: positive anti-neutrophil cytoplasmic antibodies (ANCA) may help in diagnosis of Wegener's granulomatosis, but a negative ANCA test does not rule it out. In addition, Wegener's granulomatosis and mucormycosis can co-exist, especially in a patient treated with immunosuppressants for Wegener's granulomatosis.
Bacterial brain abscess
No differentiating signs and symptoms.
Aspiration and culture of abscess fluid is positive for bacteria.
Ecthyma gangrenosum
Necrotic-appearing lesions on the skin, sometimes with surrounding erythema, occurring typically in the presence of pseudomonal sepsis. Similar host populations are vulnerable.
Culture of lesions is positive for bacteria.
Fusariosis
Patients with fusariosis have a high incidence of skin lesions as a manifestation of disseminated disease in >50% to 60%, as opposed to <5% to 10% in mucormycosis. [24]Lesions are clinically indistinguishable from mucormycosis.
High incidence of positive blood cultures (>50% of patients) as opposed to rare positive blood cultures in mucormycosis (<5%). [24]

Multiple endocrine neoplasia syndromes

Familial medullary thyroid cancer
Negative family history of MEN syndrome.Multiple family members >50 years of age are affected by medullary thyroid cancer without phaeochromocytoma.
Specific RET proto-oncogene mutations for familial medullary thyroid cancer (FMTC). [27]
Hyperparathyroidism-jaw tumour syndrome
Strong family history of hyperparathyroidism-jaw tumour syndrome.Parathyroid carcinoma develops in 10% to 15% of affected patients.
Raised calcium levels (can be in the range of 3.25-3.5 mmol/L [13-14 mg/dL]).Genetic testing for HRPT2 gene germline mutations. [52]
Isolated familial hyperparathyroidism
Negative family history of MEN1. [53]However, up to 20% of families with isolated familial hyperparathyroidism (IFHPT) do have MEN1 gene mutations, which suggests modifying genetic factors may be protecting those families against other MEN1 tumours. [1]
Genetic testing for MEN1 gene mutations. However, this may be insufficiently sensitive, meaning patients require continued monitoring for late appearances of non-parathyroid tumours characteristic of MEN1.
Sporadically occurring primary hyperparathyroidism
Age of onset for sporadic cases is up to 30 years later than for MEN1. [54]
MEN screening (performed if unusual features exist, e.g., family history, young age at presentation.)
Familial hypocalciuric hypercalcaemia
Positive family history.Generally asymptomatic.
Calcium clearance to creatinine clearance ratio <0.01 (tested when vitamin D replete and in the absence of interfering medications, such as thiazide diuretics).Lifelong elevated serum calcium levels in index cases and family members.Parathyroid hormone may be elevated.
Isolated familial pituitary tumours
Usually familial somatotropinomas that are distinguished from sporadic acromegaly by positive family history. [55]
Genetic testing may reveal mutations in arylhydrocarbon receptor-interacting protein genes (found in some families with isolated pituitary tumours).
Carney's complex
Spotty skin pigmentation, cardiac myxomas, and pigmented adrenal cortical hyperplasia. [56]Abnormal skin pigmentation may be the first sign at birth. Lentigines usually assume their characteristic distribution later.Related cardiac myxoma signs and symptoms include symptoms of right or left ventricular failure, syncope, haemoptysis, Raynaud's phenomenon, murmurs, elevated jugular venous pressures, and/or pyrexia.
Genetic testing may reveal inactive mutations in the gene encoding for protein kinase A type 1A regulatory subunits (present in >60% of patients). [57]

Multiple myeloma

Monoclonal gammopathy of unknown significance
Asymptomatic condition. No end-organ damage (bone lesions, anaemia, hypercalcaemia, renal dysfunction). [14]
Bone marrow biopsy shows <10% of monoclonal plasma cells. The monoclonal component on serum electrophoresis <3 g/dL, no proteinuria. [30]
Solitary plasmacytoma
Localised bone pain or soft tissue swelling.
Presence of monoclonal plasmacytosis on biopsy of the lesion (bone or soft tissue), without evidence of plasma cells on bone marrow biopsy. No other osteolytic lesions on skeletal survey, except the diagnostic lesion.
Waldenstrom's macroglobulinaemia
No bone pain. Frequently presents with symptoms of hyperviscosity, such as mucosal bleeding and neurological, ocular, and cardiovascular abnormalities. Also presents with organomegaly and lymphadenopathy.
Serum electrophoresis shows IgM >30000 mg/L (3 g/dL). Presence of lymphocytes or plasmacytoid lymphocytes on bone marrow biopsy and skeletal survey is negative. Patients may have evidence of increased serum viscosity.
Amyloidosis
Fatigue and weight loss are common symptoms. Hepatomegaly and macroglossia occur in more than 30% of patients, and renal insufficiency occurs in 50% of patients. Possible nephrotic syndrome, congestive heart failure, orthostatic hypotension, carpal tunnel syndrome, and peripheral neuropathy are some other presenting features.
Exclude with bone marrow biopsy that should show fewer than 5% monoclonal plasma cells.
Heavy chain disease
Most common presenting symptoms are weakness, fatigue, and fever, associated with lymphadenopathy and hepatosplenomegaly.
Characterised by the presence of a portion of the Ig heavy chain in the serum or urine or both. Also associated with the presence of lymphoplasmacytic marrow infiltrate.
Lymphoma, non-Hodgkin's
Presenting symptoms may include fever, night sweats, and weight loss. Presenting signs are spleen and lymph node enlargement.
Lymph node biopsy is diagnostic. Lymphocytic infiltrate may occur in the bone marrow. Peripheral blood flow cytometry may be suggestive of clonal lymphocytosis.

Multiple sclerosis

Myelopathy due to cervical spondylosis
The patient's symptoms and signs are all below the neck (although they may have dizziness and headache).
MRI of the cervical spine shows compression of the spinal cord.
Fibromyalgia
Symptoms are vague, with generalised weakness and non-specific fatigue common.Neurological examination is normal apart from possible functional overlay.
MRI brain may show non-specific white matter changes, but not the characteristic MS findings.
Postural orthostatic tachycardia syndrome with or without cervicogenic migraine
History is significant for headaches and dizziness, particularly with change of head position or standing. Examination is normal.
MRI of the cervical spine may show cervical spondylosis.Tilt table testing may be abnormal.
Sleep disorders
Patient describes nonrestful sleep with variable features of snoring, restless legs, and apnoea. Memory changes and mood disturbances may be prominent. Neurological examination is normal.
Abnormal sleep study.
Sjogren's syndrome
Symptoms of dry eyes and dry mouth as well as joint stiffness and pain. Neurological examination is usually normal.
Elevated autoantibodies (anti-Ro/SSA and anti-La/SSB).MRI brain and spinal cord are normal.
Vitamin B12 deficiency
Numbness, fatigue, and possible memory loss. Posterior column loss of sensation (vibration and proprioception) in the presence of increased reflexes on examination.
Low vitamin B12 level, high methylmalonic acid level.MRI does not show characteristic lesions of MS.
Ischaemic stroke
History indicates sudden onset of symptoms. Signs and symptoms usually explainable on the basis of a single neurological lesion, rather than multiple.
CT head shows ischaemic changes.Diffusion-weighted MRI will be abnormal in the acute setting.
Peripheral neuropathy
Loss of sensation and reflexes in the feet and hands.
Abnormal electromyelogram (EMG).Blood tests for specific cause (e.g., haemoglobin A1c [HbA1c] or TSH) are abnormal.
Lymphoma
Patient has gradual onset of severe disability.
MRI shows persistent enhancing lesion over time, which may worsen despite treatment.Neoplastic cells seen on CSF cytology.
Inherited disorders such as mitochondrial diseases and leukodystrophies
Patient has gradual onset of memory or cognitive problems, sometimes in the setting of neuropathy.
MRI appearance is quite distinct and includes prominent symmetrical white matter changes and normal spinal cord MRI.Some blood tests are available for specific disorders.
Guillain-Barre syndrome
Loss of reflexes with predominantly motor symptoms. Dangerous respiratory complications are more common.
MRI is normal.CSFshows characteristic cytoalbumin disassociation, and the classical MS findings of oligoclonal bands and elevated IgG and IgG synthesis are absent.
Amyotrophic lateral sclerosis (ALS)
Mixed upper and lower motor neuron signs are present: increased reflexes (upper motor neuron) with atrophy and fasciculations (lower motor neuron).Visual changes are absent.ALS may involve dysphagia and pulmonary function abnormalities, but the dysphagia, unlike in MS, is usually accompanied by tongue fasiculations and dysphonia.
EMG is diagnostic of ALS. It is normal in MS unless there is a co-morbidity such as diabetes or B12 deficiency.Compressive lesions may resemble ALS and MRI of the spinal cord is recommended to exclude compressive syndromes; if MS is present, characteristic lesions are usually seen on MRI.Muscle biopsies are useful to exclude primary muscle pathology.
Systemic lupus erythematosus (SLE)
Patient may have fevers, joint pain and swelling, muscle tenderness, (malar) rash.
Elevated ANA (however, it is common to have mild elevation in MS), positive anti-DS DNA.

Mumps

Parainfluenza
Usually causes an acute respiratory infection with fever, coryza, pharyngitis, and cough. Pneumonia can also develop. [1] Less likely than mumps to cause parotitis.
Serology testing or viral culture is diagnostic.
Coxsackievirus
Often causes hand-foot-and-mouth disease as well as herpangina (illness with ulcerative lesions on the posterior oropharyngeal structures). Haemorrhagic conjunctivitis can occur. More severe complications include myocarditis, pericarditis, and encephalitis. [1] Less likely than mumps to cause parotitis on epidemic scale.
Serology testing or viral culture is diagnostic.
Acute HIV infection
Can cause an acute illness with fever, malaise, lymphadenopathy, and maculopapular rash. [1]
Positive HIV serum testing.
EBV
Causes infectious mononucleosis, characterised by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several human tumours, including Burkitt's lymphoma, Hodgkin's disease, and B-cell lymphoma. [1]
Positive heterophile antibodies.
Influenza A
Abrupt onset of headache, fever, chills, myalgias, and malaise with accompanying respiratory tract signs. Influenza has seasonal fluctuation, occurring in the winter months most commonly. [1]
Viral isolation from throat swabs, nasopharyngeal washes, or sputum.
Acute suppurative parotitis
Acute bacterial infection of the parotid gland, most commonly caused by Staphylococcus aureus. [1]
Ultrasound demonstrates findings consistent with abscess. S aureus from culture of aspirate from duct orifice.
Sjogren's syndrome
Chronic inflammation of the salivary glands. Also causes excessive dryness in the eyes, mouth, nose, vagina, and skin.
Positive rheumatological blood studies, including ANA, Sjogren's syndrome (SS)-A, SS-B antibodies, RF.
Parotid duct obstruction
Obstruction of the flow of saliva out of the parotid gland, causing pain and inflammation. Can be from a variety of causes, such as stones and tumours.
X-rays for stones may be helpful.

Muscle cramps

Tetany
Produces a characteristic motor posture known as carpopedal spasm.Hypocalcaemic tetany: tingling begins around the mouth and in the peripheral extremities then increases in intensity and spreads proximally. A sensation of spasm or tension follows the same pattern as the tingling, eventually producing a tonic spasm. If severe, proximal and paraspinal muscles may be involved. Laryngeal muscles are commonly involved early. On examination, positive Troussea's sign and Chvostek's sign are suggestive of neural hyperexcitability.
Typical clinical findings with an associated electrolyte abnormality (either hypocalcaemia, hypomagnesaemia, or alkalosis).There may also be hypokalaemia or hyperkalaemia.Electromyogram findings: individual motor units discharge independently at a rate of 5 to 25 Hz (each discharge is a group of ≥2 identical potentials).
Tetanus
Primary symptoms are muscular rigidity and spasms. Trismus and dysphagia are typical.The spasms, which are extremely painful, are caused by sudden, involuntary contractions of opposing muscles that last for only a few seconds but occur repeatedly for minutes.Spasms are localised or generalised and can be triggered by sensory stimuli, movement, or emotion.In some cases, spasms are severe enough to cause muscle injury or to fracture bones.
Diagnosed clinically.No specific change found in blood, urine, or cerebrospinal fluid (CSF).No specific confirmatory laboratory test (absence of serum tetanus toxin or a negative result from clostridial culture testing does not rule out infection).
Occupational cramps
Muscular contractions without pain.A type of dystonia and not cramp.Task specific, arising due to repetitive or skilled use of a body part (e.g., hands [hairstylists, musicians, court reporters], mouth [musicians playing wind instruments]).Begin in adulthood. [79]
No distinguishing tests.
Neuromyotonia (e.g., Isaac's syndrome)
Predisposes to true muscle cramps.However, other clinical manifestations of this disorder of continuous muscle fibre activity are usually even more prominent.All cases of neuromyotonia have visible continuous muscle twitching (myokymia).Abnormal limb posturing, identical to carpal or pedal spasm, are characteristic and may be persistent or intermittent.There is difficulty in relaxing the muscle (which differs from true myotonia), a lack of percussion myotonia, and increased rather than decreased stiffness with continued activity.In children and young adults it progresses insidiously.
Associated with the presence of serum antibodies to voltage-gated potassium channels.
Continuous muscle fibre activity syndromes (not neuromyotonia)
Slow muscle relaxation after contraction as well as non-muscular findings (autonomic findings e.g., hyperhidrosis, hypersalivation, and hyperlacrimation).May be associated with autoimmune phenomena such as myasthenia gravis and thymoma. [80]
Electromyogram demonstrates myokymic and neuromyokymic discharges.Autoantibodies to antigens on peripheral motor neurons and autonomic fibres.
Multiple sclerosis
Characterised by affective disorders (depression, primarily), optic neuritis, nystagmus, facial myokymia, vertigo, reduced sensory function, spasticity, paraplegia, exaggerated deep tendon reflexes, gait imbalance, slurred speech, sphincter and sexual dysfunction, heat sensitivity, Lhermitte's sign (electric-shock-like sensation occurring on cervical flexion, radiating down the back and the legs), cognitive impairment, and fatigue. [81]
Magnetic resonance imaging shows white matter lesions.CSF analysis: oligoclonal bands and elevated CSF immunoglobulin (Ig)G and IgG synthesis rate may be present.Somatosensory, visual evoked, and brainstem auditory evoked potentials are prolonged.
Dystrophinopathies (e.g., Duchenne's or Becker's muscular dystrophy)
May be a family history of the condition.Loss of ability to walk by about 12 years old (Duchenne's).Contractures of hips, knees, ankles. Severe scoliosis. [78]
DNA studies may detect deletion of dystrophin gene.Abnormal electrocardiogram due to degeneration and fibrosis of posterolateral aspect of left ventricular wall.Echocardiogram may show abnormal valve and wall motion, cardiomyopathy.Serum creatine kinase levels are markedly increased.Electromyogram may reveal myopathic changes.Muscle biopsy may show variation in fibre sizes, fibrosis, and basophilic and hyaline fibres in groups.
Myotonic dystrophies
Myotonia is characterised by slowing in the relaxation of muscles after voluntary contraction or electrical stimulation.Dystrophies characterised by weakness of hand, feet, neck muscles, hollowing of temples due to masseter and temporalis atrophy.Shoulder, hip, leg weakness can lead to repeated falls.Demonstration of myotonia by sharp percussion of muscle with reflex hammer or after firm voluntary contraction.Cardiomyopathy; excessive daytime somnolence and cataracts. [78]
DNA studies may detect mutations of myotonic muscular dystrophy protein kinase (DMPK) gene.Muscle biopsy may show variability in fibre size, fibrosis, and ring fibres.Electromyogram may show myotonic discharges (repetitive firing of muscle fibres at 20 to 80 Hz with waxing/waning of the amplitude/frequency).
Satoyoshi's syndrome
Alopecia, diarrhoea, endocrinopathy with amenorrhoea, and secondary skeletal abnormalities, in addition to painful muscle spasms. [82]Syndrome usually develops between 6 and 15 years of age, with alopecia and leg spasms initially.
Clinical diagnosis.
Brody's disease
Difficulty with walking and climbing stairs.Enhanced fatigueability during exercise.Painless contractures (stiffness) during exercise.Increased exercise intolerance in cold environment. [83] [84] [85]
Muscle biopsy may be sent for analysis of microsomal calcium uptake, which shows a significant decrease compared with controls.Electromyogram shows impaired relaxation of agonist muscles, with substantial electrical activity of antagonist muscles at the same time.DNA analysis detects deficiency of gene for sarcoplasmic reticulum adenosine triphosphate-dependent calcium pump.
Swartz-Jampel syndrome
Facial malformations (microstomia, micrognathia, retrognathia, short palpebral fissures, low-set ears, short neck).Musculoskeletal signs, including myopathy, myotonia, muscle hypertrophy, restricted joint mobility, kyphosis, scoliosis, pectus carinatum, anterior bowing of long bones.Areflexia or hyporeflexia, cognitive dysfunction. [86]
DNA analysis for gene causing abnormal proteoglycan of basement membranes.
Restless legs syndrome
Urge to move legs with or without paraesthesiae when relaxing or attempting to sleep. Resolves when patient begins activity. [87] Associated muscle hardening is not usually present with restless legs syndrome.
No differentiating tests.
Growing pains
Not associated with palpable/visible hardening of muscle usually seen with cramps.Most common sites of pain are shins and calves.Pain lasts between a few minutes and a few hours.Occurs at night and usually disappears by the morning. [88]
No differentiating tests.

Muscular dystrophies

Becker muscular dystrophy
Signs and symptoms are similar to those of Duchenne muscular dystrophy (DMD), but the age of onset is usually later and the clinical involvement milder.Patients are usually able to walk throughout their teens and into early adulthood.Occasionally, patients present with CHF before complaining of muscle weakness and before diagnosis.
The diagnosis of Becker muscular dystrophy can be established by muscle biopsy that demonstrates a diminished quantity/quality of dystrophin.
Limb-girdle muscular dystrophies (LGMDs)
Before DNA and dystrophin analysis, LGMDs was often misdiagnosed as Duchenne muscular dystrophy (DMD). [13]Onset of LGMD can be at any age and is equally expressed in either gender.Initial involvement is of the shoulder and pelvic girdle muscles; however, the pattern of muscle weakness can be clinically indistinguishable from that of DMD.Calves can also be hypertrophic, and some patients walk only on their toes from infancy.Rate of disease progression is highly variable. Severe disability, muscle contractures, skeletal deformities, and need for ventilator use are common, and cardiomyopathy can occur in certain forms. [14]These patients appear to have no intellectual or cognitive impairment but have an incidence of cardiomyopathy similar to that in other muscular dystrophies. [15]
CK levels are usually lower than those in DMD.Identification of deletion or mutation of relevant gene with DNA analysis confirms the diagnosis.
Emery-Dreifuss muscular dystrophy
Musculotendinous contractures tend to be severe by comparison with muscle weakness, and the cervical spine tends to be hyper-extended with the entire spine rigid.Early contractures are seen at the neck, elbow, and Achilles tendons.Abnormal fat distribution (lipodystrophy) occurs in some laminopathies, as does humeropelvic or humeroperoneal weakness.Unlike people with Duchenne muscular dystrophy (DMD), most patients are able to walk into the third decade of life.Cardiac arrhythmias are common and often life- threatening. This is probably related to the fact that emerin is normally expressed in the adhesive junctions of the heart. [16]
Emerin or lamin A/C gene mutation is seen in DNA testing.Immunolabelling of emerin is lost in X-linked cases.Conduction defects on ECG, especially AV block at the level of the AV node.
Polymyositis
Polymyositis can occur at 4 to 7 years of age, and muscle contractures and weakness can become as severe as those of Duchenne muscular dystrophy (DMD). Muscle weakness usually occurs in the proximal muscles, especially those of the shoulder and pelvic girdles.
Diagnosis is established by characteristic muscle biopsy findings of inflammation, including mononuclear invasion of non-necrotic muscle, CD8+ cytotoxic/suppressor T cells, macrophages, and absence of perifascicular atrophy of dermatomyositis.
Static encephalopathies (cerebral palsy)
The great majority of children who walk on their toes have static encephalopathies and at least mild spasticity. In many cases the children are asymmetrically affected.Children with DMD are hypotonic and tend to be symmetrically affected.
Cerebral palsy is diagnosed clinically by the finding of CNS involvement marked by spasticity (not seen in neuromuscular diseases) as well as cognitive, motor, and sensory involvement.

Musculoskeletal lower back pain

Spinal stenosis
Numbness, weakness in lower extremities, pain radiating to buttock and leg (especially if the pain radiates beyond the knees), and neurogenic claudication. Spinal stenosis is often bilateral.
Lumbar MRI, CT, or myelography shows spinal canal narrowing.EMG shows elevated insertional activity, fibrillation/sharp waves, and lower recruitment.
Radiculopathy/sciatica
Numbness, weakness in lower extremities, pain radiating to buttock and leg (especially if the pain radiates beyond the knees). Radiculopathy/sciatica is often unilateral.
Abnormal or asymmetrical patellar, hamstring, or ankle reflex.Positive straight-leg raise test.Lumbar MRI or myelography shows disc protrusions or foraminal narrowing that impinges on nerve root(s).Lumbar CT shows foraminal narrowing; may not be able to see acute herniation because nerves or disc not visible.EMG shows elevated insertional activity, fibrillation/sharp waves, and lower recruitment.
Cauda equina syndrome
Signs and symptoms include GI/GU incontinence or retention, saddle anaesthesia, and sudden unexplained bilateral lower-extremity weakness.
MRI is the best test to show compression of cauda equina.If urinary retention is absent the likelihood of cauda equina is <1/10,000. [47]
Spinal neoplasia
May be suspected when nocturnal pain and weight loss occurs, particularly if LBP does not improve after 4 to 6 weeks of conservative treatment.
Spine x-ray may demonstrate lysis of the vertebral body or posterior elements; metastases may cause destruction of the pedicle resulting in the winking owl sign.Spine MRI may show either a lytic or blastic lesion with varying T2 signal intensity.ESR may be elevated.Bone scan can identify area of turnover possibly representing primary or metastatic disease.
Abscess, osteomyelitis, or septic discitis
Patients may present with recent urinary tract or skin infection, immunosuppression, or fever.
MRI can identify abscess, osteomyelitis, or discitis.ESR and C-reactive protein may be elevated.
Ankylosing or psoriatic spondylitis, or Reiter disease
Morning stiffness lasting >60 minutes, improvement of symptoms with physical activity, and awakening at night due to LBP may suggest these inflammatory arthritides.
A positive Schober's test showing a lack of spinal flexibility suggests ankylosing spondylitis, though this is non-specific.ESR and C-reactive protein levels may be elevated.A positive result for the human leukocyte antigen (HLA)-B27 test suggests these conditions.Pelvic and spine x-ray can show sacroilitis and bamboo spine.
Spinal compression fracture
Spine tenderness on palpation, particularly in older patients with a history of steroid treatment and/or osteoporosis.
Lumbosacral x-ray can show fractures.Spine CT can more clearly define bony pathology.
Abdominal aortic aneurysm
Pain typically presents as sudden onset of intermittent or continuous abdominal pain, radiating to the back; patient may collapse.
Ultrasound/CT of the abdomen can show the presence of abdominal aortic aneurysm.
Nephrolithiasis
Pain typically radiates towards the groin in these cases.
CT urogram and renal ultrasound results are diagnostic.
Pyelonephritis
Patients may present with costovertebral angle (CVA) tenderness and urinary symptoms of dysuria, frequency, and hesitancy; flank pain may radiate to back; fever, chills, fatigue may be present.
Positive urinalysis and/or urine culture.
Sacroiliac (SI) pathology
In addition to LBP, pain is also common in the buttocks and upper thighs.
Tenderness to palpation at the SI joint and positive result for the FABER (flexion, abduction, and external rotation) and Gaenslen's (maximal hip flexion plus contralateral hip extension) tests may suggest SI joint dysfunction.Pelvic and lumbar spine x-ray can show sclerotic changes and joint widening.Pelvic and lumbar spine CT can show sclerosis, spurring, and subluxation.

Musculoskeletal sprains and strains

Fracture
Can be easily differentiated from grade 1 and 2 sprain and strain, but difficult to differentiate from grade 3 injuries.Usually needs additional tests to differentiate.
Radiography in 2 planes usually can identify fracture and dislocations.
Cartilage injury
Difficult to differentiate clinically from joint sprain.
MRI often required. Will show intact ligaments as well as the size and extent of the cartilage injury.

Myasthenia gravis

Lambert-Eaton myasthenic syndrome (LEMS)
Prominent proximal leg and arm weakness accompanied by diminished muscle stretch reflexes that improve with brief exercise.Autonomic symptoms such as dry mouth, constipation and impotence are present in some patients.Eye muscles are occasionally involved at presentation.Respiratory failure is uncommon.Associated with small-cell lung cancer in up to 70% of patients.
Negative anti-acetylcholine receptor (anti-AchR) antibody test.Antivoltage-gated calcium channel antibodies present in more than 90% of patients.
Botulism
Symptoms similar to myasthenia gravis (MG) but there may be hypotension, bradycardia, diarrhoea followed by constipation, and urinary retention.
Repetitive nerve stimulation (RNS) at high rates (≥20 Hz) may reveal a small increment in the motor response
Penicillamine-induced myasthenia gravis
Symptoms similar to MG can occur after weeks or months of treatment. They may remit on withdrawal of the drug; recovery may be slow or incomplete.
Anti-AchR antibody test. The properties of the AchR in these patients differ from those in patients with idiopathic myasthenia gravis in terms of specificity and affinity.
Primary myopathies
Gradually progressive muscle weakness which is not fatigable.These include auto-immune inflammatory myopathies or heritable myopathies as in mitochondrial diseases, such as progressive external ophthalmoplegia, or oculopharyngeal muscular dystrophy (OPMD).Positive family history.
Muscle biopsy may reveal the diagnosis. Ragged red fibres, accumulation of abnormal looking mitochondria in sub-sarcolemmal space and COX-negative muscle fibres suggest mitochondrial diseases. [20]Mutation analysis of a short GCG repeat expansion in PABPN1 gene is diagnostic of OPMD. [21]

Mycobacterium avium-intracellulare

Pulmonary TB
Difficult to clinically distinguish TB from MAI.History of TB exposure is helpful though not diagnostic.
Difficult to distinguish MAI fibrocavitary lesions from TB on lung imaging. However, MAI tends to have thinner-walled cavities, more contiguous extension of disease, and more pleural involvement.Smears will not distinguish between types of mycobacteria.Cultures are necessary to determine type.
Other non-tuberculous mycobacteria (NTM)
Other types of NTM, such as M fortuitum or M cheloneae/abscessus, are difficult to distinguish based on symptoms.
Smears will not distinguish mycobacteria.Cultures are the most accurate way of making the distinction.
HIV-related lymphoma
Clinically difficult to distinguish from disseminated MAI.
Histopathology is required to make the diagnosis of lymphoma.Cultures will be negative unless superimposed MAI infection present.
Histoplasmosis
Fungal infection commonly seen in immunosuppressed patients.Clinically difficult to distinguish from MAI.
CXR shows solitary pulmonary nodule that rarely cavitates.Diagnosed by culture, fungal stains, serological tests for antibodies, and antigen detection. [34]
Blastomycosis
Fungal infection with similar clinical presentation to MAI.Commonly associated with skin lesions such as widespread papules or erythematous verrucous lesions.
CXR may have abnormal infiltrates.Sputum smear with fungal stains may show organism.Culture of sputum positive for fungus.Skin biopsy of lesion may show organism.
Cryptococcosis
Causes pulmonary, neurological, and disseminated disease.Pedunculated skin lesions.CNS manifestations do not rule out disseminated MAI but are more suggestive of cryptococcosis.
Peripheral and CSF cryptococcal antigen are very sensitive and specific tests.
Wasting syndrome
Occurs in HIV patients in the absence of opportunistic infections or other identifiable causes of weight loss.
Clinical diagnosis of exclusion.
Sarcoidosis
Difficult to differentiate from pulmonary MAI and hypersensitivity pneumonitis.
Bilateral hilar lymphadenopathy on CXR; lung biopsy demonstrates granulomatous tissue.

Mycoplasma infection

Typical bacterial pneumonia
Acute onset with a chill followed by a high fever and pleuritic chest pain suggests pneumococcal pneumonia.
Sputum cultures and blood cultures may be positive for Streptococcus pneumoniae or other bacterial pathogens.
Viral pneumonia
Lack of effectiveness of antibiotics.
Positive nasopharyngeal viral cultures; relative lymphocytosis in WBC.
Tuberculosis
History of immunosuppression or prolonged course of disease that is not responding to antibacterial therapy.
Sputum cultures and acid-fast baccillus smear and culture stains positive; cavity in CXR.
Pneumocystis jiroveci pneumonia
History or risk factors of HIV.
Special stain of sputum or bronchoalveolar lavage positive for Pneumocystis jiroveci.
Pulmonary embolism
Absence of fever and/or lack of response to antimicrobial therapy.
CT pulmonary angiography may demonstrate pulmonary embolism.
Inhalation/occupational lung injury
History of an exposure to chemicals or special work conditions.
Negative cultures; diffuse disease on CXR.

Myelodysplastic syndrome

Aplastic anaemia
May have history of medications that cause aplastic anaemia; otherwise, symptoms may be the same.
The marrow is hypocellular for age and precursors are morphologically normal. There is no clonal chromosomal abnormality.
HIV infection
History of HIV infection or activities that increase the risk of contracting HIV.
HIV testing is positive.Bone marrow may show some dysplastic cells, with erythroid and granulocytic precursors and megakaryocytes, but this is not usually a persistent finding and will change on repeat aspirate or biopsy.
Acute myelogenous leukaemia
More likely to have symptomatic cytopenia.
Significant cytopenias, 20% blasts or greater, and on cytogenetic analysis, karyotypes t(8;21), t(15,17) and/or inv(16) and variants are present. [13]
B12 deficiency anaemia
None.
Increased neutrophil lobulation along with macrocytosis. Also low to low-normal vitamin B12 levels.
Myelofibrosis
Typically, have splenomegaly and may have hepatomegaly and a more insidious clinical course. However, this distinction may be difficult in some patients.
Bone marrow biopsy shows reticulin fibrosis, which may be found in myelodysplasia, but in myelofibrosis there is no dysplasia of all the cell lines.
Large granular lymphocytic disease
None.
T cell clone present on flow cytometry, diagnosis confirmed by PCR.
Bone marrow toxicity secondary to azathioprine
May be undergoing treatment for lupus or rheumatoid arthritis.
Reassess bone marrow aspirate for resolution of abnormalities after holding medication.
Bone marrow toxicity secondary to cyclophosphamide
May be undergoing treatment for lupus or rheumatoid arthritis.
Reassess bone marrow aspirate for resolution of abnormalities after holding medication.
Bone marrow toxicity secondary to cytotoxic therapy (especially with alkylating drugs)
History includes exposure to these medications.
Reassess bone marrow aspirate for resolution of abnormalities after holding medication. [14]
Heavy metal poisoning (particularly arsenic)
History includes possible exposure, often occupational.
Sideroblastic anaemia with no other marrow abnormalities and no abnormalities in other cell lines (normal platelets, WBC), abnormal heavy metal testing. [15]

Myelofibrosis

Polycythaemia vera
Aquagenic pruritus (itching after a shower), plethora.
RBC mass and plasma volume elevated.
Essential thrombocythaemia
Erythromelalgia, ocular migraine.
Peripheral blood leukoerythroblastosis in primary myelofibrosis (PMF).
Chronic myelogenous leukaemia (CML)
May be no differences in signs and symptoms.
Bone marrow aspiration and biopsy with flow cytometry and cytogenetic analysis, BCR-ABL fusion signal by fluorescence in situ hybridisation or PCR.
Myelodysplastic syndrome (MDS)
Absence of splenomegaly.
Bone marrow aspiration and biopsy with flow cytometry and cytogenetic analysis: dysplastic bone marrow with variable degrees of peripheral blood cytopenia (with or without monocytosis) suggests MDS.
Mast cell disease
Dermatographia or skin rash.
Serum tryptase level: elevated.
Malignant histiocytosis
May be no differences in signs and symptoms.
Bone marrow aspirate and biopsy: infiltration by malignant histiocytes.
Acute myelogenous leukaemia
Symptoms (constitutional, bleeding, infections) are more acute. Moderate to massive splenomegaly is less common than in PMF.
Bone marrow aspiration and biopsy: bone marrow hypercellularity and infiltration by blasts; blasts >20%, Auer rods, morphological description of type of blast.Immunophenotyping and molecular studies: blasts express surface antigens and molecular markers that help to identify their specific lineage.Peripheral blood smear: blasts on blood film, presence of Auer rods.
Acute lymphocytic leukaemia
Symptoms (constitutional, bleeding, infections) are more acute. Moderate to massive splenomegaly is less common than in PMF.
Bone marrow aspiration and biopsy: bone marrow hypercellularity and infiltration by lymphoblasts.Immunophenotyping and molecular studies: blasts express surface antigens and molecular markers that help to identify their specific lineage.Peripheral blood smear: leukemic lymphoblasts.
Hairy-cell leukaemia
Lymphocytosis and absence of monocytes.
Bone marrow aspiration and biopsy: presence of hairy cells in the bone marrow, presence of reticulin fibres.Flow cytometry and cytogenetic analysis: positive.Peripheral blood smear: presence of hairy cells.
Hodgkin's lymphoma
Lymphadenopathy more common in lymphomas.
Lymph node biopsy: Hodgkin's cells within an appropriate background cellular milieu.
Non-Hodgkin's lymphoma
Lymphadenopathy more common in lymphomas.
Lymph node biopsy: positive for non-Hodgkin's lymphoma.
Multiple myeloma
Symptoms of hyperviscosity and bone pain.
Serum and urine protein electrophoresis (SPEP and UPEP): paraprotein spike (IgG >35 g/L [>3.5 g/dL or 3500 mg/dL] or IgA >20 g/L [>2.0 g/dL or 2000 mg/dL]) and light chain urinary excretion >1 g/day); hypogammaglobulinaemia.Serum and urine immunofixation assay (IFE): increased concentrations of free light chain.
Hyperparathyroidism
May be no differences in signs and symptoms.
High-normal to elevated calcium, decreased vitamin D, high-normal to elevated PTH.
Renal osteodystrophy
May be no differences in signs and symptoms.
Urea, creatinine: elevated.Radiological studies: osteopenia.
Vitamin D deficiency
May be no differences in signs and symptoms.
Decreased vitamin D levels.
Systemic lupus erythematosus (SLE)
Skin, joint, and mucosal manifestations of SLE.
Positive ANA, and anti-double-stranded DNA.
HIV Infection
Opportunistic infections.
Anti-HIV antibody: positive.CD4 count: decreased CD4 count.Presence of HIV viral load.
Tuberculosis
Cough and haemoptysis.
Positive tuberculin skin testing, abnormal CXR, and positive microbiological tests.
Metastatic cancer in the bone marrow
May be no differences in signs and symptoms.
CT scans, bone survey, tumour markers: indicate metastatic spread.

Myocarditis

Acute coronary syndrome
Patients presenting with MI tend to be older and have traditional risk factors for coronary atherosclerosis when compared with patients with myocarditis.
Left heart catheterisation should reveal significant coronary atherosclerotic disease.
Dilated cardiomyopathy
There can be considerable overlap between dilated cardiomyopathy and myocarditis. As many as 16% of patients presenting with acute dilated cardiomyopathy who undergo endomyocardial biopsy are found to have biopsy-confirmed myocarditis. [36]A family history of dilated cardiomyopathy, a known history of exposure to a direct cardiotoxin (e.g., ethanol), or the absence of elevations of markers of myocardial injury make myocarditis less likely.
The presence of an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischaemic damage associated with CAD is diagnostic for myocarditis. However, the lack of these findings does not exclude myocarditis.
Pericarditis
It can be difficult, if not impossible, to distinguish patients presenting with pericarditis from those with myocarditis based on history and physical examination alone.Both syndromes can exhibit typical or positional chest pain, and both are commonly preceded by a fever and/or a viral syndrome.The presence of signs or symptoms of heart failure suggests myocarditis as the aetiology, as isolated pericarditis does not impair left ventricular (LV) function.
Two-dimensional echo can be used to help differentiate these conditions. The presence of LV dysfunction (systolic or diastolic) implicates myocarditis as the aetiology.
Stress-induced cardiomyopathy (broken heart syndrome, Takotsubo cardiomyopathy)
Patients with stress-induced cardiomyopathy can present similarly to those with acute myocarditis.A history of an acute emotional or physical stressor within the prior 2 weeks with a rather rapid clinical deterioration supports a diagnosis of stress-induced cardiomyopathy. [37]Rapid recovery back to baseline within 4 to 8 weeks is the rule for stress-induced cardiomyopathy, the occurrence of which supports its diagnosis.
No specific test will distinguish stress-induced cardiomyopathy from myocarditis.

Nappy rash

Allergic contact dermatitis
There may be no difference in signs and symptoms.
Patch testing to determine offending antigenic allergen.
Seborrhoeic dermatitis
Erythematous papules and plaques associated with yellow scales in nappy area and cradle cap.
Clinical diagnosis. Testing not usually required.
Psoriasis
Thick silvery scales in groin and gluteal cleft, accompanied by nail abnormalities.
Clinical diagnosis. Testing not usually required.
Granuloma gluteale infantum
Macerated skin with purple papulonodular lesions.
Clinical diagnosis. Testing not usually required.
HIV
Recalcitrant rash in nappy area; recurrent infections; other symptoms and signs of this disease.
Positive HIV antibody screen.
Nutritional deficiencies
Recalcitrant rash in nappy area and peri-oral area; failure to thrive, developmental delay; alopecia; behavioral abnormalities.
Low levels of deficient nutrient (i.e., zinc, biotin, protein).
Immune deficiencies
Severe, recalcitrant rash associated with generalised eczema, failure to thrive, recurrent infections.
Abnormal immunological work-up, specific to underlying disorder.
Langerhans cell histiocytosis
Chronic scaly papules and nodules in groin, face, trunk; palm and sole involvement; symptoms of other organ involvement.
Skin biopsy reveals Birbeck granules.
Urea cycle defect
Recalcitrant nappy rash associated with peri-oral involvement; developmental delay; metabolic derangements.
Abnormal serum amino acid analysis, elevated serum ammonia level associated with a normal anion gap and a normal serum glucose level are found in urea cycle defects.
Child abuse and neglect
Scalded skin, bruising, or object-shaped lesions in nappy area; poor hygiene; developmental delay.
Clinical diagnosis. Testing not usually required.

Narcolepsy

Untreated sleep apnoea
Patients often snore, snort, gasp for air, or choke during sleep.Features pre-disposing to sleep apnoea, such as large neck circumference, high body mass index, crowded oropharynx, glossomegaly.
Polysomnogram (PSG) plus positive airway pressure (PAP) titration.PSG shows loud snoring, elevated arousal index and an apnoea-hypopnoea index of ≥5.PAP (continuous PAP or bi-level PAP) titration: a progressive increase in PAP level eliminates the apnoeas, hypopnoeas, and snoring; improves arousal index; and normalises the oxygenation and/or flow contour.
Periodic limb movements of sleep
Excessive daytime somnolence (EDS) in the absence of cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis.
PSG usually shows periodic limb movement index >20.
Restless legs syndrome (RLS)
Typical symptoms in adults and children >12 years old include an urge to move the legs. Usually accompanied or caused by uncomfortable sensations in the legs. [1] [2]Symptoms begin or worsen during periods of inactivity, are worse at night, and are partially or totally relieved by movement.Children may present with a biological parent with RLS.
No need for PSG, unless to exclude other conditions.Distinguished by typical clinical presentation. Children may have a polysomnographic periodic leg movement index >5/hour of sleep.
Behaviourally induced insufficient sleep syndrome
Sleep hx, patients report getting better after oversleeping or catching up sleep.Lack of features of narcolepsy.
Diagnosis is clinical. No differentiating test.
Hypersomnia due to medicines
Hx of medicine use.Temporal association of symptoms with use of medicine.
No need for PSG, unless to exclude other conditions.Challenge/withdraw/re-challenge.
Hypersomnia due to known physiological condition
Medical hx (e.g., hydrocephalus).
Diagnosis is clinical. No differentiating test.
Hypersomnia associated with psychiatric conditions
Psychiatric history, for example, of depression or of anxiety.
Treatment of underlying condition solves the EDS.
Idiopathic hypersomnia
Naps do not improve EDS and are typically unrefreshing; long habitual sleep duration in some patients; sleep inertia or “drunkenness” (inability or extreme difficulty in morning awakening).Lack of features of narcolepsy.
Diagnosis of exclusion.Can include short or long habitual sleep duration.PSG and multiple sleep latency test (MSLT) often needed to exclude other conditions.MSLT finds shortened sleep latency with (usually) <2 sleep-onset rapid eye movement periods.
Kleine-Levin syndrome
Recurrent episodes of EDS of 2 to 14 days' duration, at least yearly and associated with behavioural changes but normal cognition, alertness, and behaviour between the attacks.Lack of features of narcolepsy.
Diagnosis is clinical. No differentiating test.
Menstrual-related hypersomnia
Occurs exclusively in women.Episodes start after menarche, last up to 1 week, occur almost monthly, with rapid resolution at the time of the menses.Lack of features of narcolepsy.
Diagnosis is clinical. No differentiating test.Hypersomnia responds to hormonal therapy.

Nasal polyps

Neoplasm (benign or malignant)
Features that may suggest neoplasm include unilateral symptoms, epistaxis/bleeding, crusting, cacosmia (perception of foul odour), periorbital oedema, displaced globe, double or reduced vision, ophthalmoplegia, severe frontal headaches, frontal swelling, signs of meningitis or focal neurology, and systemic symptoms such as weight loss.
CT head defines extent and characteristics of the lesion(s). MRI can be performed in conjunction with CT for further evaluation.Biopsy confirms histology.
Congenital lesions (e.g., encephalocele, concha bullosa)
No differentiating symptoms.
CT and MRI head defines extent and characteristics of the lesion(s).
Foreign body
Usually sudden onset of unilateral symptoms. Epistaxis may feature.
Nasendoscopy may allow identification and possible retrieval of foreign body.CT head may identify position, shape, and nature of foreign body.

Nausea and vomiting in pregnancy

Viral gastroenteritis
Limited course of illness. May be associated with diarrhoea. Fever may be present.
Diagnosis is clinical.
Food poisoning
Hx of travel or exposure to possible contaminated food. Often associated with abdominal pain or cramps, diarrhoea, and fever.
Stool culture for enteric pathogens such as Salmonella, Shigella, and Campylobacter organisms.
Cholecystitis
RUQ pain, worse after fatty meals. RUQ tenderness to palpation. Positive Murphy's sign (the examiner's hand rests along the costal margin, and deep inspiration causes pain).
Positive RUQ ultrasound for gallstones.May have elevated LFTs.
Hepatitis
May be associated with jaundice. RUQ pain frequent. Palpable liver edge, which is tender to palpation.
Elevated LFTs.Signs of hepatic inflammation on RUQ ultrasound.Viral serology positive if infectious cause.ANA positive if autoimmune hepatitis a cause.
Acute pancreatitis
RUQ pain and/or epigastric pain frequent.
Elevated amylase and lipase. Signs of pancreatic inflammation on RUQ ultrasound.
Acute appendicitis
RLQ pain consistent. Low-grade fever typical.
FBC shows leukocytosis.Ultrasound suggestive of inflamed appendix.
Acute pyelonephritis
History of frequency, urgency, dysuria. History of fever. Costovertebral angle tenderness.
Urinalysis shows pyuria.Positive urine culture.
Kidney stones
Colicky abdominal pain. History of blood in urine. Costovertebral angle tenderness.
Haematuria on urinalysis.Ultrasound shows calcification within urinary tract.
Hyperthyroidism
History of heat intolerance, palpitation, dry skin. Enlarged and possibly tender thyroid on palpation. Thyroid nodules on palpation.
Decreased TSH and elevated T4.
Pseudotumor cerebri
Presence of headache, pulsatile tinnitus, diplopia, and visual loss.
CT scan of brain fails to demonstrate mass and is consistent with increased intracranial pressure.
Vestibular lesions
Presence of balance disturbances and vertigo. Tinnitus may be present.
Diagnosis is clinical.
Migraine headaches
Severe headaches with presence of phonophobia and photophobia. Hx and/or FHx of migraine headache.
Diagnosis is clinical.
CNS tumours
Presence of neurological findings (e.g., headache, visual disturbance, focal neurological signs).
Intracranial mass on CT.
Acute fatty liver of pregnancy
Onset during the third trimester. Fever and jaundice occur in up to 70% of women. [15]
Elevated LFTs and bilirubin with elevated WBC count.

Necrotising fasciitis

Cellulitis
Systemic toxicity should be absent or minimal. [5]
Absence of major abnormalities in FBC and serum biochemistry.
Impetigo
Patchy distribution of superficial blistering, with or without bullae, with crusting and erythema. May be asymptomatic or with pruritus.
Culture of infected tissue identifies Staphylococcus aureus or Streptococcus pyogenes. [5]
Erysipelas
Painful bright red, tender plaque with clear margins. [5]
Culture of infected tissue identifies S pyogenes or other streptococci. [5]
Myositis
No involvement of skin or soft tissue. Swelling over involved area is present but may not be painful. Unusual to see systemic signs/symptoms of toxicity. [9]
Ultrasound or CT/MRI to identify focal involvement of muscle with swelling.MRI can also identify oedema. [9]
Gas gangrene
Rapidly progressive infection with Clostridium. Usually follows severe penetrating trauma or crush injury with interruption of blood supply to the affected area. Can be difficult to differentiate clinically. [5]
Culture of infected tissue identifies Clostridium. [5]
Cutaneous anthrax
History of intravenous drug use, or contact with animals or their products (e.g. hides, wool). Painless, pruritic papule forms 2 to 5 days after exposure. Lesion becomes vesicular, evolving into a necrotic black eschar with massive surrounding oedema 24 to 36 hours later. Regional lymphadenopathy is common.
Vesicular fluid/blood Gram stain and culture: gram-positive bacilli in short chains (Bacillus anthracis); flat, non-haemolytic mucoid colonies on 5% sheep's blood agar.Punch biopsy of cutaneous lesion: necrosis of the dermis and epidermis, oedema, and mild inflammatory infiltrate; abundant bacillary fragments (prior to antibiotic therapy); Bacillus anthracis (post-antibiotics).

Neonatal jaundice

Carotenaemia
Yellow colour seen mostly in palms and soles but not seen in sclera and mucous membranes.
Total serum bilirubin levels will be normal. Increased serum carotene levels.

Nephrolithiasis

Acute appendicitis
Usually presents with right lower quadrant pain, fever, and signs of peritonitis.
Urinalysis is negative.Non-contrast helical CT scan (NCCT) shows dilation of appendix and absence of renal stones.
Ectopic pregnancy
Woman of childbearing age presents with missed menstrual period, right lower quadrant pain, or pelvic pain with some degree of vaginal bleeding or spotting. Cervical motion tenderness may be present on pelvic examination.
Urine pregnancy test is positive and serum hCG elevated.Ultrasound reveals presence of mass in fallopian tubes.
Ovarian cyst
May present with lower pelvic/abdominal discomfort and/or dyspareunia; may be cyclical.Palpable mass on pelvic examination.
Abdominal ultrasound shows cystic adnexal lesion; free fluid in the peritoneum.NCCT shows absence of renal stones.
Diverticular disease
May present with left lower quadrant pain or abdominal pain as opposed to flank pain.
Technetium pertechnetate scan may show enhancement of diverticulum if gastric mucosa is present.NCCT shows absence of renal stones.
Bowel obstruction
Bowel obstruction patients present with abdominal distension, vomiting, and ileus.
Abdominal x-ray may show volvulus.NCCT shows collapsed bowel with proximal dilation and absence of renal stones.
Acute pancreatitis
History of gallstones or alcohol abuse.These patients typically have epigastric pain that typically radiates to the back, as opposed to flank pain.
NCCT shows inflammation of the pancreas and absence of renal stones.The diagnosis of pancreatitis can usually be distinguished from renal stones on clinical grounds, but in rare cases it might be necessary to measure serum amylase and lipase, which are raised in pancreatitis and usually normal in stone disease.
Peptic ulcer disease
May or may not have a history of peptic ulcer disease. Pain is abrupt, severe in intensity, and may be localised to right lower quadrant; often related to eating meals.
Erect CXR and abdominal x-ray may show free air under the diaphragm.Endoscopy shows peptic ulcer.NCCT shows absence of renal stones.
Gastroenteritis
These patients typically have diffuse abdominal pain and no flank pain. Vomiting is prominent and patient may have diarrhoea.
In patients with bloody diarrhoea, stool specimen is positive for culture.NCCT shows absence of renal stones.
Abdominal aortic aneurysm
Pain typically presents as sudden onset of intermittent or continuous abdominal pain, radiating to the back; patient may collapse.
Ultrasound/CT of the abdomen can show the presence of abdominal aortic aneurysm.
Pyelonephritis
Patients may present with costovertebral angle tenderness and urinary symptoms of dysuria, frequency, and hesitancy; flank pain may radiate to back; fever, chills, fatigue may be present.
Positive urinalysis and/or urine culture.

Neurally mediated reflex syncope

Orthostatic syncope (postural or orthostatic intolerance syncope syndromes)
Clinical historical clues to suggest this form of syncope include fainting with concomitant dehydration, antihypertensive medication or vasodilator use, and patients who are old and frail or have underlying conditions associated with autonomic failure. Symptoms that are reproduced with carotid sinus massage (CSM) are not consistent with orthostatic syncope.
Orthostatic BP measurement: a fall in BP (usually >50 mmHg systolic), associated with symptoms of syncope or near syncope. The patient may exhibit the hypotension immediately after standing or it may evolve over the subsequent 3 to 5 minutes of upright quiet posture. Notably, this observation may not be reliably reproduced, especially in older people. Repeated or 24-hour ambulatory measurements may be necessary to elucidate this diagnosis.Tilt-table test: hypotension on standing.
Bradycardia as primary cause of syncope
Syncope is possible with long sinoatrial nodal pauses or very slow heart rates.Occurs owing to bradycardia-induced cerebral hypoperfusion, especially in the setting of left ventricular (LV) dysfunction.Common in patients with complete heart block and a very slow ventricular escape rhythm with LV dysfunction, and in patients with second-degree AV block.
ECG: may show sinus bradycardia with or without sinus arrhythmia, AV block with junctional or ventricular escape, His-Purkinje system disease, bradycardia, and AV block in a setting of myocardial infarction; deep T-wave inversions across the precordium indicative of a neurological event may occur in conjunction with sinus bradycardia.Electrophysiological (EP) testing: may be helpful in some cases, but the findings are usually non-specific. It may show quantitative measurement of sinus node, AV node, or His-Purkinje system dysfunction.
Bradycardia: AV conduction disorders as primary cause for syncope
Paroxysmal or persistent AV block can cause severe bradycardia and thereby lead to syncope.
ECG: patient may have Mobitz type 2 second-degree AV block, third-degree AV block, or alternating left and right bundle branch block; other observations that suggest an AV conduction disorder as the cause of syncope, but are at best considered to be only indirect evidence, include 1) bifascicular block (left bundle branch block, right bundle branch bock with left anterior or left posterior fascicular block), 2) Mobitz type 1 second-degree AV block in older people (usually defined as >70 years old).Mobile cardiac outpatient telemetry: provides long-term ECG monitoring and thereby increases the chance of detecting ECG abnormality (i.e., AV block, possibly transient) if an arrhythmia is the cause of symptoms.Implantable loop recording: shows evidence of AV block.EP testing: in the absence of a direct symptom-arrhythmia correlation, a tentative diagnosis can be made in case of ventricular pauses >3 seconds in duration when the patient is awake or if Mobitz type 2 second-degree or third-degree (i.e., complete or high-grade) AV block is discovered. In the setting of nothing more than bifascicular block or non-specific intraventricular conduction delay, invasive EP study may be helpful. On the other hand, these patients often also have underlying structural heart disease, so it is equally important to look for both the conduction abnormalities and susceptibility to tachyarrhythmias.
Supraventricular tachycardias as primary cause of syncope
Very rapid heart rates; infrequently causes a sufficient period of prolonged hypotension to cause syncope; patients may complain of near syncope; reduced circulating volume status (i.e., relative dehydration), upright posture, presence of structural heart disease (especially with diminished ejection fraction or significant valvular or other outflow obstruction), and abnormal reflexes of the peripheral vasculature.
ECG: shows heart rate variability and microvolt T-wave alternans.Holter monitoring, loop recording, or EP studies: may demonstrate findings of supraventricular tachycardias.
Ventricular tachycardia (VT) as primary cause of syncope
Usually occurs in setting of ischaemic heart disease, valvular heart disease, or certain dilated cardiomyopathies that may result in symptomatic hypotension; similarly, VT in obstructive cardiomyopathies and arrhythmogenic right-ventricular dysplasia may cause syncope; torsade de pointes VT is a characteristic feature of the long-QT syndromes, arrhythmia may be very fast and often is self-terminating.
ECG: shows wide QRS complex (≥120 milliseconds), rate >120 bpm lasting for ≥3 beats, spontaneously resolving in <30 seconds.Echocardiogram: shows compromised LV function, evidence of structural heart disease, or hypertrophic or idiopathic cardiomyopathy.
Non-sustained VT (NSVT) as primary cause of syncope
NSVT is a common finding during assessment of syncope (whether by Holter or extended-duration ambulatory ECG monitoring) but is diagnostically a much less specific finding than sustained VT.
ECG: shows wide QRS complex (≥120 milliseconds), rate >120 bpm lasting for ≥3 beats, spontaneously resolving in <30 seconds.Echocardiogram: absence of structural cardiac disease.The isolated presence of NSVT, particularly in the absence of evident structural cardiac disease or ECG evidence of a channelopathy, should not be considered a causative diagnosis. However, if hypotension occurs with NSVT during EP study, or if monomorphic sustained VT is reproducibly inducible, a basis for syncope seems likely. [19]
Bradycardia or tachycardia: sinus node dysfunction as primary cause of syncope
Lightheadedness, weakness, palpitations, dyspnoea, angina; bradycardia; CSM provokes a sinus pause >3 seconds; heart rate does not change with Valsalva manoeuvre.
ECG: shows sinus pauses >3 seconds.Holter monitoring: indicates sinus pauses >3 seconds, which would indicate bradycardia or tachycardia-bradycardia syndrome. Used for patients with paroxysmal symptoms.Loop recorder: shows sinus pauses >3 seconds, which would indicate bradycardia or tachycardia-bradycardia syndrome. Used for patients with paroxysmal symptoms.EP study: measures sinus nodal recovery time by overdrive suppression of the sinus node and sinoatrial conduction time.
Acute coronary syndromes (ACS) as primary cause of syncope
Chest pain, palpitations, dyspnoea, weakness, and lightheadedness.Pale, diaphoretic; may have low BP; heart rate may be brady- or tachycardic; audible S3 or S4; jugular venous distension if right ventricular failure from inferior wall myocardial infarction; signs of CHF such as peripheral oedema and bibasilar rales.
ECG: may show ST-segment elevation or depression, dynamic T-wave changes.Cardiac enzymes: may show elevated troponin and creatine kinase-MB.Chest x-ray: may show increased alveolar markings; cardiomegaly. Pulmonary oedema causes increased alveolar markings and can be caused by ischaemia secondary to ACS. Cardiomegaly suggests concomitant CHF.Echocardiography: may show wall motion abnormalities, decreased ejection fraction.Coronary angiography: may show vessel obstruction or coronary anomalies.
Acute aortic dissection as primary cause of syncope
Chest and back pain, tearing in nature; hypotension; unequal pulses or BP in 2 arms; acute pulmonary oedema; focal neurological sign of weakness, dysarthria, or cranial nerve defects if carotid arteries involved.
ECG: shows ST- and T-wave ischaemic changes. Cardiac ischaemia occurs if low dissection involving the coronary arteries.Chest x-ray: will indicate widened mediastinum.Transoesophageal echocardiography: may show false lumen or flap in the ascending or descending aorta, new aortic regurgitation, or pericardial tamponade.CT chest with contrast: may show false lumen or flap in the ascending or descending aorta.
Severe pulmonary hypertension as primary cause of syncope
Dyspnoea, fatigue, chest pain, palpitations, leg oedema, right-sided third heart sound, right-sided fourth heart sound, pulmonic regurgitation, palpable left parasternal heave, jugular vein distension, peripheral oedema, cyanosis.
Chest x-ray: shows attenuated peripheral vascular markings (pruning), enlarged pulmonary artery shadows, and opacification of the retrosternal space on the lateral view.ECG findings of right ventricular hypertrophy: tall R wave and small S wave (R/S ratio >1) in lead V1, qR complex in V1, rSR' in V1, a large S wave and small R wave (R/S ratio <1) in V5 or V6, or a S1S2S3 pattern; right-axis deviation: mean frontal plane QRS axis >100°; right atrial enlargement: P wave ≥2.5 mm in leads II, III, and aVF.
Pulmonary embolism as primary cause of syncope
Dizziness, shortness of breath, pleuritic chest pain, tachycardia, tachypnoea, hypotension, loud P2, jugular venous distension, right ventricular lift.
ECG: shows sinus tachycardia; presence of S1, Q3, and T3; usually non-specific.D-dimer: non-specific if positive; pulmonary embolism excluded if negative. Utility is in its negative predictive value.Chest x-ray: shows decreased perfusion in a segment of pulmonary vasculature (Westermark's sign) and/or presence of pleural effusion.CT pulmonary angiography: identifies any thrombus in the pulmonary circulation.
Aortic stenosis as primary cause of syncope
Exertional dyspnoea, angina, dizziness, and syncope; in late stages develops into CHF (dyspnoea, paroxysmal nocturnal dyspnoea, peripheral oedema); harsh ejection systolic murmur that radiates to carotids, murmur loudest at the left sternal edge and on squatting, and softer with Valsalva and isometric exercises; slow rising pulse; low carotid volume; S4 with systolic thrill; signs of CHF (pulmonary rales, lower extremity oedema, jugular venous distension, and hepatomegaly).
ECG: shows LV hypertrophy and/or ST depression from LV strain.Chest x-ray: indicates cardiomegaly and/or pulmonary oedema. Aortic stenosis can cause LV hypertrophy and pulmonary oedema.Echocardiography: assesses the valve area (severity of stenosis), mean AV gradient, LV hypertrophy, ejection fraction.
Hypertrophic obstructive cardiomyopathy as primary cause of syncope
Systolic ejection murmur (audible at the lower left edge; accentuated by exercise and standing; lessened by lying supine or squatting), dyspnoea, angina.
ECG: shows left-axis deviation and prominent Q waves in inferior and lateral leads.Echocardiography: shows asymmetrical septal hypertrophy; systolic anterior motion of anterior mitral valve leaflet; reversed E:A ratio with diastolic dysfunction; left atrial enlargement.EP studies: show inducible ventricular arrhythmias and/or conduction abnormalities.Cardiac catheterisation: will show increased LV outflow tract gradient directly related to severity of obstruction and increased LV filling pressures.
Vertebrobasilar transient ischaemic attack (TIA) as primary cause for syncope
Vertebrobasilar TIA is more likely than carotid-distribution TIAs to present as apparent syncopal episodes but, overall, is extremely rare. Furthermore, vertebrobasilar TIAs are usually marked by other symptoms (e.g., vertigo) indicative of posterior circulation compromise.
MRI: shows brainstem infarction.Carotid Doppler ultrasonography: shows vertebrobasilar stenosis.CT head: brainstem not well visualised; may have chronic ischaemic changes or evidence of previous infarction. Not a sensitive test for detecting brainstem ischaemia. Commonly used modality because of widespread availability and ease of detecting haemorrhage.Magnetic resonance angiography (MRA): shows stenosis of vertebrobasilar artery.
Subclavian steal as primary cause for syncope
Subclavian steal is a rare condition and a very rare cause of syncope. Symptoms tend to occur when patients are exercising using the affected arm. Because of its rarity, it should be considered only when other causes have been eliminated.
Duplex ultrasonography: shows retrograde blood flow in the vertebral artery.
Migraine as primary cause for syncope
Associated with basilar artery migraine; premonitory aura terminates in loss of consciousness, which is slow in onset; occipital headache associated with diplopia, vertigo, tinnitus, visual changes, and syncope; strong association with menstrual cycle; no significant physical finding on examination.
MRI and MRA: should be normal and are used to exclude other pathologies.
Non-syncope transient loss of consciousness (T-LOC)
This category mainly comprises 3 conditions: epilepsy, metabolic, and endocrine disturbances.Epilepsy is predominated by abnormal movements and complex behaviour patterns; epileptic seizures do not depend on the posture and can occur while the patient is supine; epilepsy is often preceded by an aura or strange sensations, which is not the case with true syncope; after an epileptic seizure, the patient will typically be confused or may have a focal weakness, whereas after a syncopal episode the patient promptly regains their mental and physical faculties (although they may feel fatigued). Temporal lobe seizures are the form of epilepsy most often confused with syncope because they can either mimic or cause reflex bradycardia and hypotension.Metabolic and endocrine disturbances that can cause non-syncope T-LOC include diabetic coma, hypoglycaemia, and hypercapnia.
Interictal EEG: may be normal.
Adrenal insufficiency, adrenal crisis
Hyperpigmentation of the skin, abdominal pain, hypotension; related to stressors such as surgery.
Cortisol and adrenocorticotropic hormone stimulation test: must be interpreted by an endocrinology specialist.
Hypoglycaemia
Recovery with glucose intake.
Serum glucose: low.
Seizures
Prolonged jerky movements, tongue biting, urinary or faecal incontinence, prolonged post-ictal period.
EEG: shows epileptiform activity or focal, localising abnormality.Prolactin level: must be interpreted by a neurology specialist.
Alcohol ingestion
Vomiting, staggering gait, slurred speech.
Alcohol level: high or positive.
Stroke
Focal neurological deficit, slurred speech, prolonged reduction in awareness.
Head CT: shows hypoattenuation (darkness) of the brain parenchyma; loss of grey/white matter differentiation, and sulcal effacement; hyperattenuation (brightness) in an artery indicates clot within the vessel lumen.MRI brain: shows acute ischaemic infarct.
Narcolepsy
Excessive daytime sleepiness despite adequate sleep.
Overnight polysomnogram: often shows snoring, frequent awakenings, reduced sleep efficiency, periods of rapid eye movement (REM) sleep within the first 20 minutes of sleep, and multiple arousals.Sleep latency test: shows sleep latency ≤8 minutes plus ≥2 sleep-onset REM periods.
Cataplexy
Loss of muscle tone, often triggered by strong emotions, slurred speech, knee buckling, without loss of awareness.
Sleep history.Sleep actigraphy.Polysomnogram.Sleep latency test.All must be interpreted by specialists in the relevant field.
Pseudosyncope
Generalised anxiety disorder, panic disorder, somatisation disorder, and major depression can present with apparent syncope; usually young; no known cardiac problems; frequent episodes of recurrent syncope; no specific exam findings.
Tilt-table test: negative.Video EEG: result must be interpreted by a neurology specialist.

Neuroleptic malignant syndrome

Sepsis
CNS or systemic signs/symptoms of infection.Sepsis may be the primary diagnosis but may also be present (later in course) as a complication of NMS. Sometimes concurrent infections (e.g., respiratory or UTI) may further complicate diagnostic assessment. [6] [12] [35]
Blood and urine cultures are performed.
Drug abuse/adverse reaction
Hx of drug abuse, overdose symptoms.
Diagnosis is usually based on history and physical examination. Stopping all possible and appropriate medications is important.
Catatonia
Withdrawal, predominance of motor abnormalities, absence of fever, gradual evolution of presentation, potential hx of prior episodes.
Diagnosis is usually based on history and physical examination.
Serotonin syndrome
Rapid onset after administration of a serotonergic drug, hyperkinesia, clonus.
Diagnosis is usually based on history and physical examination.
Mania
Patients usually present with marked agitation and confusion.
Diagnosis is usually based on history and physical examination.
Malignant hyperthermia
Occurs in genetically susceptible people following exposure to anaesthetics or depolarising muscle relaxants; rapid onset, trismus.
Diagnosis is usually based on history and physical examination.
Heat stroke
Rapid onset, occurs during episodes of prolonged elevations in ambient temperatures.
Diagnosis is usually based on history and physical examination.
Metabolic conditions
Various metabolic effects (e.g., dehydration, hyponatraemia, hypokalaemia) can cause delirium presentation.
Basic and extended metabolic panels are performed.
Brain infarcts
Often mimic NMS.
CT/MRI and EEG are performed.
Normal pressure hydrocephalus
Slowing of gait, urinary urgency.
CT/MRI and EEG are performed.
Brain tumours
Often mimic NMS.
CT/MRI and EEG are performed.

Nevi

Melanoma
Tends to be >6 mm, more irregularly bordered, more asymmetrical, haphazardly multi-coloured, with pink, red, white, brown, black, and blue components. [5] Referral to a dermatologist is encouraged if the clinician has any doubts in distinguishing a nevus from a melanoma. Excluding malignant change in nevi or de novo melanoma may be challenging, especially when distinguishing from dysplastic or Clark's nevi.
Dermatoscopy: ramified streaks of asymmetrical pigment, black pepper-grain dots, bulbar pseudopods, blue-whitish veils, depigmented areas, multi-coloured pattern, milky red globules, irregular hairpin vessels, ulceration, asymmetrical follicular openings, and rhomboid structures on the face. [30] View imageHistopathology: loss of organised nested melanocytes, and an increase in single melanocytes, often in a pagetoid pattern in the epidermis, with pleomorphism, cytological atypia, and mitotic figures.
Seborrhoeic keratosis
Waxy, 'stuck-on' papules, often multiple, that increase in number over the age of 30 years.
Dermatoscopy: comedo-like follicular pseudo-openings; horny pseudocysts, fissures, and crypts, fingerprint-like patterns, uniform hairpin vessels, and pigment pseudo-network on the face. [30]Histopathology can also distinguish.
Solar lentigo
Flat, brown macules and patches on sun-damaged skin.
Dermatoscopy: moth-eaten borders with an even brown reticular pattern.Histopathology can also distinguish.
Simple lentigo
Small, flat, brown macules clinically very similar to junctional nevi, found on non-sun-damaged skin.
Dermatoscopy: small, evenly pigmented, brown, reticular pattern.Histopathology can also distinguish.
Ephelis (freckle)
Multiple flat, light-brown, sun-exposed macules, usually on the face, upper back, dorsal arms, and chest.
History and physical examination can usually distinguish.Dermatoscopy: similar to a solar lentigo but smaller in size.Histopathology can also distinguish.
Cafe-au-lait macule
Small-to-large, flat, brown homogenous macules or patches with a well-defined and regular border, present since birth and unchanged, with exception of growth proportional to the person.
History and physical examination can usually distinguish.Histopathology can also distinguish.
Pigmented basal cell carcinoma (BCC)
Arising on sun-exposed skin, the pigmented variant of BCC has irregular blue-grey pigment, tends to be asymmetrical, and may be ill-defined.
Dermatoscopy: structureless areas; maple leaf-type structures; branch-like telangiectasias; large, ovoid, blue-greyish nests; radial areas; and ulceration. [30]Histopathology can also distinguish.
Dermatofibroma
A firm, dome-shaped, often hyperpigmented or pink papule, often on the lower extremities of young adults, and thought to be induced by trauma (e.g., insect bite).
Dermatoscopy: central white, scar-like area with pigment at the periphery.Histopathology can also distinguish.
Haemangioma
A red-to-purple, dome-shaped, soft papule.
Dermatoscopy: blood-filled, red-blue lacunae.Histopathology can also distinguish.

Night blindness

Myopia
Difficulty seeing in poor illumination is often noticed when driving at night. Myopia causes distant objects to appear blurry and unfocused, while nearby objects remain in focus. Myopic shift can occur at low levels of light and may be mistaken for night blindness. [18]
Eye test will reveal that the patient is myopic and requires a glasses prescription.
Glaucoma
Patient will often be receiving treatment for glaucoma. Patients may be otherwise asymptomatic.
Tonometry will reveal raised intra-ocular pressure. Examination of optic disc shows an increase in optic nerve head cup-to-disc ratio.Visual field testing is used to detect any visual field loss.
Optic neuropathy
Patients with optic neuropathy often have unilateral loss of vision, impairment of colour vision, relative afferent papillary defect, peri-orbital pain, optic disc swelling, and other neurological abnormalities.
Visual field examination may reveal a central field defect.Radiological investigation may reveal optic nerve pathology.MRI findings support the diagnosis of optic neuritis and rule out other causes of optic nerve damage such as compressive neuropathy.
Cataract
Blurring of vision either unilateral or bilateral. Often increasing age and associated glare symptoms.
Slit-lamp examination will reveal cataract.
Age-related maculopathy
Patients with early age-related maculopathy may experience difficulty seeing in low illumination due to impaired photoreceptor function. [19]
Slit-lamp examination will show changes at the macula.

Nocardiosis

Tuberculosis
Clinical differentiation is difficult. In immunocompetent patients, cavities are more frequently related to tuberculosis. In immunocompromised patients, particularly patients with AIDS, cavities are less frequently associated with tuberculosis and very common in nocardiosis. [21]
Mycobacterium can be differentiated from Nocardia in clinical samples, since mycobacteria do not stain well with Gram stain and modified acid-fast stain. They are also microscopically different from Nocardia. [5]
Actinomycosis
Clinical differentiation is difficult.
Actinomyces can be differentiated from Nocardia in clinical samples, since Actinomyces is not stained by modified acid-fast stain. [5]
Lung abscess
Clinical differentiation is difficult.
Evidence of Nocardia species in sputum or other specimens allows differentiation.
Brain abscess
Clinical differentiation is difficult.
Evidence of Nocardia species in clinical specimens allows differentiation of these organisms from others in the differential diagnosis, but sometimes invasive procedures (e.g., stereotactic brain biopsy) are necessary to confirm or rule out disseminated nocardiosis. [41] [44] [45]
Pulmonary and disseminated opportunistic fungal infections
Clinical differentiation is difficult.
Evidence of filaments, detection of fungal antigens or nucleic acids, and fungal cultures in sputum or other specimens allow differentiation.

Non-allergic rhinitis

Allergic rhinitis (seasonal, perennial, mixed)
May have positive FHx, symptoms around cats/dogs/furry pets, seasonal response. More likely to present early in life, before age 35.
Skin prick testing or specific IgE testing to aeroallergens will be positive; eosinophils will be elevated in peripheral blood.
Nasal polyposis
Loss of olfaction. Polyps may be evident on PE.
CT scan of sinuses reveals polyps.
Deviated septum
Unresponsive to medicines. Possibly evident on PE.
Seen on CT scan of sinuses or on nasal endoscopy.
Hypertrophic turbinates
Unresponsive to medicines.
Seen on CT scan of sinuses.
Adenoidal hypertrophy
Unresponsive to medicines.
Seen on CT scan of sinuses.
Anatomic variants in osteomeatal complex
Unresponsive to medicines. May have hx of numerous sinus infections.
Seen on CT scan of sinuses.
Foreign body
Unresponsive to medicines, possibly hx of inserting object into nares. Might be visible on PE.
Seen on CT scan or nasal endoscopy.
Choanal atresia
Unresponsive to medicines. History of syndrome (where the choanal openings are not developed and are blocked).
Seen on CT scan.
Nasal tumour
Possible to have headaches, anosmia and other constitutional symptoms (e.g., cachexia, weight loss, lymphadenopathy), or patients can be refractory to medications with persistant symptoms. May have mass and/or lymphadenopathy on PE.
Mass seen on CT scan of sinuses; nasal endoscopy.
Wegener's granulomatosis
May rarely cause prolonged and progressive sinusitis, leading to loss of cartilage in nose and a typical pug-nosed appearance.
Biopsy lesion.
Sarcoidosis
20% will have upper airway involvement, primarily in the nasal cavity.
Biopsy shows granuloma.
Upper respiratory infection
May have fever, chills, cough and shortness of breath.
Most often caused by respiratory viruses; influenza antigen testing may be appropriate in season, otherwise diagnosis is clinical.
CSF rhinorrhoea
Clear rhinorrhoea.
Sample of nasal discharge for protein, glucose and cell count will reveal findings typical for CSF.
Sinusitis, acute
May have fever, chills, headache and sinus pressure.
Sinus CT reveals inflammation, opacification of sinuses.
Sinusitis, chronic
May have fever, chills, headache and sinus pressure.
Sinus CT reveals inflammation, opacification of sinuses.
Intranasal drug abuse-induced rhinorrhoea
Hx of intranasal drug abuse. Patient may have septal perforation, atrophy of the nasal mucosa, or mucosal ulcertations.
Urine drug testing.
Oestrogen related
Pregnancy or oestrogen supplementation (including oral contraceptives) may be present in history.
Pregnancy test if applicable.
Hyperthyroidism
May have no symptoms, or may have palpitations, unexplained weight loss, increased appetite.
TSH low, free T4 high.
Hypothyroidism
May have no symptoms, or may have unexplained weight gain, low energy, changes in hair and skin texture.
TSH high, free T4 low.
Side effect of beta blockers
Hx of beta blocker use.
Resolves with holding beta blockers.
Adverse reaction to aspirin
Hx of aspirin use.
Resolves with holding aspirin.
Topical decongestant rebound effect
History of recent discontinuation or irregular usage of topical decongestants.
Resolves with consistent decongestant use or complete cessation.

Non-cholera Vibrio infections

Sepsis
Can be caused by many different pathogens. There are no differentiating signs and symptoms.
Blood culture may provide the aetiological agent. Other sign/symptom-directed test (i.e., CT abdomen) may provide the source of sepsis.
Gangrene
Can be caused by infection or ischaemia. There are no differentiating signs and symptoms.
Blood culture may provide the aetiological agent.
Infectious diarrhoea
Differential diagnosis is broad, as various bacteria, parasites, and viruses cause diarrhoea. There are no differentiating signs and symptoms.
Presence of specific infectious agent on stool or serological testing.

Non-diabetic hypoglycaemia

Idiopathic postprandial syndrome (pseudohypoglycaemia)
Clinical history of hypoglycaemic symptoms after ingesting a meal.
Glucose level >3.3 mmol/L (>60 mg/dL) in presence of symptoms.
Insulin autoimmune hypoglycaemia
Extremely rare condition that usually spontaneously resolves.
Can assay for insulin antibodies as well as antibodies to insulin receptors. [34]

Non-Hodgkin's lymphoma

Hodgkin's lymphoma
Bimodal age distribution at diagnosis (peaks at mid-20s and mid-60s), pruritus, and alcohol-triggered pain. Very difficult to differentiate clinically.
Lymph node biopsy (Reed-Sternberg cells are characteristic). [29]
ALL
Acute onset, purpura, bleeding, and infection are key presenting symptoms.
Blood smear (blasts), bone marrow biopsy (blasts), flow cytometry, and immunochistochemistry (tumour cell markers), cytogenetics, PCR.
Infectious mononucleosis
A self-limiting condition that occurs in young adults (high school and university students). There is generally abrupt onset of symptoms including pharyngitis, rash, and myalgias.
Heterophile antibody test (monospot) positive, EBV titres elevated, polyclonal B-lymphocyte population on flow cytometry.
Hepatitis C (HCV)
History of IV drug use, HIV, multiple transfusions; abdominal pain, nausea, symptoms of liver disease and malaise; can be asymptomatic.
Antibody-HCV (enzyme-linked immunosorbent assay [ELISA]) or recombinant immunoblot assay, RT-PCR for HCV RNA.
Cytomegalovirus infection (CMV)
Immunocompromised host (e.g., post-transplant); cough, bone pain, visual symptoms, and diarrhoea are common presenting features.
CMV titres (elevated), CMV PCR, rectal biopsy for CMV.
Tuberculosis
Not always easy to differentiate clinically, but patient may have risk factors for tuberculosis (e.g., HIV positive, history of drug use, inadequate nutrition, inner city population), cough, malaise, and weight loss.
CXR, CT chest, purified protein derivative of tuberculin, acid-fast bacillus test, TB culture, pleural/peritoneal fluid analysis (in some cases), pleural biopsy (in some cases), bone marrow biopsy (in some cases).
HIV infection
Risk factors for sexually transmitted disease (e.g., multiple sexual partners, unprotected sexual intercourse), history of IV drug use, multiple transfusions before 1985, prior flu-like illness and rash.
ELISA (screen), Western blot (confirm), RT-PCR for HIV RNA (viral load) are diagnostic.
Syphilis infection
Consider risk factors for STD; prior genital chancre and rash.
Treponema-non-specific tests: rapid plasma reagin, Venereal Disease Research Laboratory (VDRL); Treponema-specific tests (fluorescent treponemal antibody absorption [FTA-ABS]; micro-haemagglutination Treponema pallidum [MHA-TP]) are diagnostic.
Sarcoidosis
Young or middle-aged, cough, dyspnoea, skin lesions, Bell's palsy, and malaise; may be asymptomatic.
CXR, CT chest (hilar adenopathy), bronchoscopy with biopsy of lymph nodes (non-caseating granulomas).
Rheumatoid arthritis
More common in females; joint symptoms (pain, swelling, heat, stiffness).
Rheumatoid factor (IgM antibody) elevated titre; ESR elevated; synovial fluid analysis.
Systemic lupus erythematosus (SLE)
Much more common in females; characteristic rash (may be butterfly type), photosensitivity, skin lesions, oral ulcers, myalgia, arthritis, and neurological symptoms.
ANA, anti-double-strand DNA, anti-Sm antibodies, abnormal FBC, proteinuria; American Rheumatology Association (ARA) criteria for diagnosis. [30]

Non-small cell lung cancer

Small cell lung cancer
Typical features include cough, haemoptysis, chest pain, dyspnoea and hoarseness (if recurrent laryngeal nerve paralysis). Frequently unwell-looking, short of breath, with signs of recent weight loss.Finger clubbing and hypertrophic osteoarthropathy may be present but is less common in small cell lung cancer compared with NSCLC.Usually wheezing from underlying COPD or bronchial obstruction, crackles due to post-obstructive pneumonia or atelectasis or diminished breath sounds from bronchial obstruction are present unless early disease.Facial and upper extremity swelling, distended neck veins, and dilated collateral vessels may indicate compression of the superior vena cava.Features related to distant metastases (e.g., bone pain and/or pathological fractures from bony metastases; confusion, personality change, seizures, weakness, focal neurological deficits, nausea and vomiting, and headaches from brain metastases).Brachial plexus involvement can cause weakness and/or atrophy of the intrinsic muscles of the hand and paraesthesias and/or pain in a C8/T1 distribution. Can impact the sympathetic chain causing Horner's syndrome (ptosis, meiosis and ipsilateral anhidrosis).
CT chest often shows massive lymphadenopathy and direct mediastinal invasion, common features of small cell lung cancer.Sputum cytology is a non-invasive and relatively simple diagnostic method with high specificity but low sensitivity, and the cost may outweigh the usefulness in terms of patient management.Flexible bronchoscopy plus biopsy provides pathological confirmation of diagnosis. Endobronchial masses can be biopsied with forceps. Endobronchial brushings, washings and alveolar lavage increase the diagnostic yield. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes is now possible. Detection of small peripheral lesions (<2 cm) is improved by use of endobronchial ultrasound.
Metastatic cancer
Symptoms will relate to the site of the primary tumour and there may be general symptoms of pain, weight loss, malaise, cough, dyspnoea, clubbing, and focal wheezing. Physical findings may or may not be present depending on nature and stage of tumour.
CT chest shows one or multiple nodules of variable sizes from diffuse micronodular shadows (miliary) to well-defined masses. Often irregular and often in the periphery of the lower lung zones.Sputum cytology may reveal characteristic malignant cells. Yield is higher with large endobronchial lesions or large masses.CT/MRI head, abdomen and pelvis: extrapulmonary cancers that commonly metastasise to the lung include melanoma, thyroid carcinoma, oesophageal cancer, ovarian cancer, sarcomas and adenocarcinomas of the colon, breast, kidney and testicle.PET-FDG scan shows increased uptake in nodules and at primary site. In metastatic disease, PET scan aids in the identification of the primary site and allows for appropriate staging whenever malignancy is confirmed. Certain metastatic lesions have a lower probability of 18-fluorodeoxyglucose (FDG) uptake, such as renal cell carcinoma.Flexible bronchoscopy and biopsy shows characteristic malignant cells. Bronchoscopy has a 100% yield for endobronchial lesions.CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells in some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
Pneumonia/bronchitis
Clinical and radiological features of bronchitis or pneumonia should improve with appropriate treatment.Recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer.
CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray.Bronchoscopy can also be used to assess for endobronchial lesions or biopsy suspicious pulmonary masses.
Organising pneumonia (cryptogenic organising pneumonia or bronchiolitis obliterans organising pneumonia)
Normally presents as an influenza-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, non-productive cough, malaise, dyspnoea, and weight loss. Sometimes features pleuritic chest pain and haemoptysis.In most patients, auscultation reveals fine, dry lung crepitations. Finger clubbing is unusual.
CT chest is preferable to plain chest x-ray as it gives a better assessment of the disease pattern and distribution and potential sites for biopsy. Typical features include patchy 'ground-glass' opacities in a subpleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilatation; 3-5 mm diameter centrilobular nodules or other ill-defined nodules; mediastinal lymphadenopathy; pleural effusions.Pulmonary function tests typically show a restrictive pattern.Bronchoalveolar lavage (BAL) shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages and occasional plasma cells. CD4+/CD8+ cell ratio is decreased. Also, the ratio of lymphocytes to CD8+ cells is significantly increased.Transbronchial lung biopsy, in combination with BAL can be a useful approach, prior to possible open biopsy.Open lung biopsy is often required for definitive diagnosis.
Pulmonary tuberculosis
Cough longer than 2 to 3 weeks, discoloured or bloody sputum, night sweats and weight loss, loss of appetite, pleuritic chest pain.
Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates. Ipsilateral adenopathy, atelectasis from airway compression and pleural effusion can be seen. Reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe or superior segment of either lower lobe, with or without cavitation. As disease progresses it spreads to other segments/lobes.Sputum smear: positive for acid-fast bacilli (AFB). Sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis). Organisms other than M tuberculosis, especially non-tuberculous mycobacteria (e.g., M kansasii and M avium), may be positive for AFB stain.Nucleic acid amplification tests (NAAT) positive for M tuberculosis. DNA or RNA amplification tests for rapid diagnosis. May be used on sputum or any sterile body fluid. Several commercial tests are available. Results available in less than 8 hours in the laboratory. Useful in smear positive disease to confirm that observed mycobacterium are M tuberculosis (95% sensitivity, 99% specificity) and in smear-negative disease for rapid diagnosis (50% sensitivity, 95% specificity). In suspected smear-negative cases, a moderate to high pretest probability should guide the decision to use NAAT.
Sarcoidosis
Cough, dyspnoea, fatigue, weight loss, fever, night sweats, rash, eye pain, photophobia, blurred vision, red eye. Pulmonary examination is usually unrevealing. Can affect any organ, so physical findings depend on specific organs affected. Skin lesions including maculopapular eruptions, subcutaneous nodular lesions and red-purple skin lesions.
CT chest: adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, though can be located throughout the lung.Flexible bronchoscopy and biopsy reveals presence of non-caseating granulomas. The identification of granulomas on tissue obtained by bronchoscopy should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy. The identification of granulomas on tissue obtained by TTNA should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.Laboratory markers: ACE elevation may be seen in sarcoidosis, but is non-specific and adds very little information.
Infectious granuloma
History may include travel to endemic areas, pet/animal exposures and specific leisure activities (e.g., caving).May feature cough, dyspnoea, haemoptysis, weight loss, fever, joint aches, skin lesions and night sweats. Many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium spp, zygomycetes, and others.Non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis. Lymphadenopathy with active disease.
CT chest typically shows lesions <2 cm diameter with round, smooth borders. May have central, laminated or diffuse calcification patterns if lesions are old. Sometimes mediastinal lymphadenopathy with or without lymph node calcifications. Angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium spp. and zygomycetes) can be seen as nodules with 'halo sign' or ground-glass opacity surrounding a nodule. Occasionally, calcifications can be seen in the spleen or liver.Fungal serologies: positive during active infection. The exact role of fungal serologies in assessing lung nodules is unclear; however, they provide valuable evidence of exposure to histoplasmosis, cryptococcosis, aspergillosis, coccidioidomycosis, and mucormycosis.Flexible bronchoscopy and biopsy can provide sample for identification and culture and sensitivity of organism.CT-guided TTNA can provide biopsy from some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks and local expertise.PET-FDG scan: usually negative (<2.5 standardised uptake values). May be falsely positive in active infectious processes.
Amyloidosis
Weight loss, paraesthesias, dyspnoea and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms; weight loss of >9 kg is common. Small vessel involvement can cause jaw claudication, calf and limb claudication and, rarely, angina. Amyloid purpura is present in around 1 in 6 patients, typically periorbital. Eyelid petechiae are common. Hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree.
CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions or diffuse alveolar deposits.Serum immunofixation shows presence of monoclonal protein; seen in 60% of patients with immunoglobulin light chain amyloidosis (AL).Urine immunofixation shows presence of monoclonal protein; seen in 80% of patients with amyloidosis.Immunoglobulin free light chain assay shows abnormal kappa to lambda ratio. This relatively new test has extremely high sensitivity, over 90%, for diagnosing amyloidosis.
Rheumatoid arthritis
Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain and deformity.
CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones. May show cavitation.Flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule. The identification of granulomas on tissue obtained should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause. Necrobiotic nodules present as a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often being centred on necrotic inflamed blood vessels.Laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported.
Wegener's granulomatosis
Cough, chest pain, dyspnoea, haemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain.
CT chest shows solitary or multiple lung nodules. Airways are frequently affected.Flexible bronchoscopy shows presence of necrotising granulomatous inflammation. The identification of granulomas on tissue obtained by bronchoscopy or TTNA should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.CT-guided TTNA can provide access to some lesions inaccessible to flexible bronchoscopy.Laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA) detected. ANCA testing results depends on the extent and severity of the disease. Generalised Wegener's granulomatosis has >90% C-ANCA or PR-3 positive. Limited Wegener's granulomatosis has 60% ANCA positive.
Non-Hodgkin's lymphoma
Aggressive NHL lymphoma may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological exam. Low-grade NHL patients often minimally symptomatic or asymptomatic.
CT chest: frequently anterior mediastinum. Can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures.FBC with differential shows thrombocytopenia, pancytopenia.Blood smear shows nucleated red blood cells, giant platelets.Lymph node biopsy with immunohistochemistry shows characteristic cells. Preferably obtain excisional or core biopsy to provide information on lymph node architecture.
Hodgkin's lymphoma
Predominantly a disease of young adults. Most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain.
Plain chest x-ray typically shows mediastinal mass/large mediastinal adenopathy.PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging. Sensitivity reported to be 93% and specificity 87%.Lymph node biopsy with immunohistochemistry: the Hodgkin's cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell.
Carcinoid tumour
Often asymptomatic with normal physical examination. May cause cough, dyspnoea, haemoptysis, unilateral wheezing, or post-obstructive pneumonia if tumour is endobronchial.
CT chest: 80% of carcinoid tumours appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and highly vascularised.Flexible bronchoscopy shows raised, pinkish, vascular, lobulated lesions. Presence of malignant cells is diagnostic. Endobronchial forceps biopsy is usually required; bronchial brushings, sputum specimens and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis.
Tracheal tumours
Common symptoms include dyspnoea, cough, haemoptysis, wheeze, and stridor. Less commonly, hoarseness and dysphagia may be present.
Plain chest radiographs are generally insensitive for detection of tracheal tumours. Clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing and post-obstructive pneumonia or atelectasis.Helical CT enables accurate calculation of tumour volumes and can help differentiate mucosal lesions from submucosal lesions.MRI can be useful in assessing extension into surrounding tissue and vascular anatomy.Bronchoscopy allows direct visualisation, opportunity for biopsy and potential for laser treatment.
Thyroid mass
Symptoms and signs depend on size of mass. May be visible/palpable as lump on anterior aspect of neck. May present with dysphagia, hoarseness, difficulty breathing and pain in neck or throat. May also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass.
Laboratory testing should include thyroid function panel, with TSH, free T4, and free T3.I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism. A hyperfunctioning (hot) nodule is almost always benign. Most nodules are hypofunctioning (cold). Most of these are benign, but malignant nodules are also cold.Ultrasound and Doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s). Features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity or irregular margins. It can also guide fine needle aspiration, which can reveal malignant cells or cyst fluid.CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer and extension of the scan into the chest can help evaluate a retrosternal thyroid mass.
Hamartoma
Usually asymptomatic with no physical findings. About 1% to 20% of lesions can be endobronchial and can cause dyspnoea, wheezing or recurrent infections, secondary to airway obstruction.
CT chest shows well-demarcated peripheral nodule, average diameter of 1.5 cm with heterogeneous appearance due to its content of mesenchymal tissue. Fat attenuation is common, with or without calcification. 'Popcorn' calcifications can occur in 20% of cases. Imaging findings classic enough to be considered diagnostic.
Arteriovenous malformation (AVM)
Dyspnoea is uncommon. May cause haemoptysis, pulmonary bruit, arteriovenous communications or haemorrhagic telangiectasia in the skin, mucous membranes and other organs. Cyanosis and finger clubbing. Neurological symptoms from cerebral aneurysms, cerebral emboli.
CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified. Most common in lower lobes. Multiple lesions in 30% of cases. Usually round or oval, ranging in size from 1 to several cm in diameter.Pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures. In cases of significant haemoptysis, pulmonary angiogram is combined with bronchial artery embolisation.Arterial blood gas analysis may show decreased PO2 and decreased oxygen saturation when AV flow is severe. In cases of severe systemic AVMs, the chronic hypoxaemia may cause polycythaemia.
Bronchogenic cyst
Usually diagnosed in infancy and childhood, although 50% diagnosed after 15 years of age. Approximately 50% of patients are asymptomatic. In adults, chest pain (often pleuritic) and dysphagia (due to oesophageal compression) are the most common symptoms. May also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression and pneumothorax.
2-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina. Can appear as a solid tumour or show air-fluid level if cyst is infected or contains secretions.CT chest: frequently middle mediastinum, typically at level of the mediastinum. Cysts are thin-walled with smooth borders and may contain secretions, blood or pus. Calcifications may also be seen.MRI: frequently middle mediastinum, typically at level of the mediastinum. On T2-weighted images, shows as a homogeneous mass of moderate to bright intensity. On T1-weighted images, lesions may vary in their intensity depending on protein content of the cyst.
Thymoma/thymic carcinoma
Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis. May also present with cough, chest pain, signs of upper airways congestion, superior vena cava syndrome, dysphagia or hoarseness. May have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis and Sjogren's syndrome. Around 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision).
Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography.CT chest: 90% occur in anterior mediastinum. CT is usually accurate in predicting tumour size, location and invasion into vessels, the pericardium and the lung. However, it cannot accurately predict invasion or respectability.Positron emission tomography (PET) may be of value in determining malignancy and extramediastinal involvement.Preoperative biopsy is indicated if there are atypical features or imaging suggests invasive tumour and patient is under consideration for induction therapy.
Germ cell tumour
Occur mostly in men aged 20 to 40 years. About one third of patients are asymptomatic. Symptoms are related to the size of the lesion. May cause chest pain, breathing problems, cough and fever, headache and fatigue.
CT chest: germ cell tumours account for about 10% to 15% of mediastinal tumours in adults and 25% of such tumours in children. Frequently located in anterior mediastinum. CT can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures. Seminomas appear as large, well-marginated, homogeneous, anterior mediastinal mass with soft-tissue opacity or attenuation that shows minimal contrast enhancement.Serum tumour marker tests: alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), lactate dehydrogenase (LDH). Beta-hCG are elevated in 7% to 18% of patients. AFP levels are usually normal.

Non-ST-elevation myocardial infarction

Aortic dissection
Pain is described as a 'tearing' back pain. There may be BP differential between upper and lower extremities.Aortic dissection often occurs in patients who have collagen vascular disease (i.e., Marfan's syndrome).
Chest CT with contrast or MRI may show the dissection or an intimal flap. CXR may reveal widened mediastinum.Echocardiography may show a dissection depending on the location.
Pulmonary embolism
Patients often present with dyspnoea, pleuritic chest pain, cough, or haemoptysis. Hypoxia may be present. Lower limbs should be examined for DVT (enlarged, tender, erythematous calves).
Nuclear imaging with V/Q scans or chest CT with contrast is most often used to diagnose pulmonary embolism. High-probability V/Q scan findings are ≥2 segmental or 1 larger perfusion defect with a normal CXR.Chest CT scan may show central filling defects within the vascular lumen, tracking of contrast material around a filling defect, and/or complete occlusion. Smooth filling defects making an obtuse angle with a vessel wall may represent chronic thrombi or recent recanalisation.Pulmonary artery angiography is the diagnostic standard. Positive findings include a filling defect or sharp cut-off of the artery. A tram-track appearance is described in the presence of non-occlusive emboli.
Peptic ulcer disease
Pain is described as burning epigastric pain that occurs hours after meals or with hunger. It often wakes the patient at night and is relieved by food and antacids.There may be a previous history of reflux or medicines that can cause peptic ulcer (i.e., recent use of steroid or non-steroidal anti-inflammatory drugs).
Endoscopy may show ulcers, erosion, or gastropathy.
Acute pericarditis
Pain is relieved by sitting forwards. Friction rub or distant heart sounds may be heard on auscultation.A history of a recent cardiac procedure (Dressler's syndrome), renal failure, or preceding illness (fever or diarrhoea) may be present.
ECG may show diffuse ST elevations.Echocardiogram and chest CT scan may show pericardial effusion. Cardiac MRI is useful and has high sensitivity for detection of pericardial effusion, loculations, and pericardial thickening.Blood tests may indicate systemic inflammation (e.g., elevated WBC count, elevated ESR or CRP). Renal failure can cause uraemic pericarditis.
Oesophageal spasm
Usually diagnosed after ruling out other causes of chest pain. A past history of oesophageal spasm is typical and there may be a precipitating event.Pain due to oesophageal spasm is often relieved by glyceryl trinitrate, making it difficult to differentiate from cardiac pain.
The oesophagus may have a corkscrew appearance on barium swallow. This represents simultaneous rings of contraction in the distal oesophagus. [43]
Costochondritis
Diagnosis is made on the history or exclusion of other causes. There may be a history of recent or repeated trauma. The pain is typically localised with point tenderness, sharp in nature, and relieved by non-steroidal anti-inflammatory drugs.
There are no specific studies or imaging to diagnose costochondritis.
Panic attack
Most often diagnosed after exclusion of other causes. Patients often have other psychiatric illness. Women are affected more than men. Panic attacks may be situational.
No tests or procedures can diagnose anxiety disorders.
Stable ischaemic heart disease
Angina pain is recurrent and reproducible with exertion, and is relieved by rest or glyceryl trinitrate.
Diagnosis is most often made on history alone. Coronary artery catheterisation may show the typical fixed coronary artery luminal wall narrowing.Intravascular ultrasound during cardiac catheterisation may reveal the typical stable plaque of stable angina (calcified, thick fibrous caps) rather than the unstable plaques (lipid-laden, thin caps) that cause acute coronary syndrome.
Myocarditis
There is a wide spectrum of presentation from asymptomatic to cardiogenic shock. Patients may present with a history of recent influenza-like illness associated with arthralgias and malaise. The symptoms of heart failure may be present.Myocarditis may be idiopathic or caused by infections (viral, bacterial, or fungal), drugs (e.g., chemotherapy agents, anti-hypertensives, and anti-epileptics), and autoimmune disorders (e.g., systemic lupus erythematosus, sarcoidosis, and rheumatoid arthritis).
The definitive test is endomyocardial biopsy, which shows lymphocyte infiltration and myocyte necrosis.Cardiac enzymes or brain natriuretic protein may be raised.Leukocytosis, eosinophilia, elevated ESR and CRP, and a rise in serum viral titres are common.
Acute cholecystitis
On physical examination there is constant RUQ pain with or without Murphy's sign (inhibition of inspiration due to pain on palpation). There may be a history of gallstones or previous episodes of biliary colic.
Ultrasound may show a distended gallbladder and gallstones. [44] If ECG changes accompany cholecystitis, these would most likely include ST elevation.
Boerhaave's syndrome
Caused by oesophageal rupture with mediastinitis. It typically follows retching or vomiting, aggravated by swallowing. Patients may have subcutaneous emphysema and a hoarse voice.
CXR shows pneumomediastinum >90% of the time. Oesophagram and CT scan can confirm diagnosis or reveal the condition. CT may show pneumomediastinum and peri-oesophageal air tracks. Oesophagram may show an oesophageal tear. [45] Endoscopy is not recommended for Boerhaave's syndrome.
Brugada's syndrome
More common in Asian people and men aged 30 to 50 years. Patients typically present after an episode of polymorphic ventricular tachycardia or a cardiac arrest.
ECG shows saddle-shaped ST elevation in leads V1 through V3. These changes are associated with complete or incomplete right bundle-branch block and T-wave inversions.

Non-sustained ventricular tachycardias

SVT with aberrant conduction
None
ECG, electrophysiological study: failure to meet criteria for NSVT; absence of fusion capture beats; absence of AV dissociation.
Electrical artifact
None
ECG: evidence of underlying sinus rhythm discernable through electrical noise (motion artifact).

Noonan's syndrome

Turner's syndrome
Hypergonadotrophic hypogonadism and abnormal karyotype.
Karyotype test will identify abnormal chromosomes.
Leopard syndrome
Presence of lentigines (liver spots) that develop with age, sensorineural deafness, and a higher likelihood of hypertrophic cardiomyopathy than in NS. [42]
Molecular genetic testing will identify different mutations in genes PTPN11 and RAF1. [5] [6] [43]
Cardio-facio-cutaneous syndrome
Severe mental retardation; coarser facial appearance than NS, which increases with age; a high frequency of structural CNS abnormalities (especially hydrocephaly and ventriculomegaly); a higher likelihood of seizures than NS; and severe and long-lived GI dysmotility. [44]
Molecular genetic testing will identify different genes (BRAF, MEK1, MEK2).Although KRAS mutations may cause both cardio-facio-cutaneous syndrome and NS, the mutations concerned are different. [44]
Costello syndrome
Moderate mental retardation, coarser facial features than NS, chaotic atrial rhythms, deep palmar and plantar creases; development of perinasal, perioral, and perianal warts; and a 10% to 15% predisposition to tumours (e.g., embryonal rhabdomyosarcoma, neuroblastoma, and transitional cell bladder cancer). [45]
Molecular genetic testing will identify mutations in HRAS, another gene in the RasMAPK pathway. [45]
Neurofibromatosis type 1
Familial cancer syndrome; hallmark features include hyperpigmented skin lesions and benign neurofibromas; learning disabilities are common. [1]
Molecular genetic testing will identify mutations in neurofibromin, another gene in the RasMAPK pathway.
Williams syndrome
Supravalvular aortic stenosis; hypercalcaemia; characteristic appearance, with periorbital fullness, long philtrum, and full lips; unique cognitive profile and typical 'cocktail party' personality.
Caused by a deletion of chromosome 7q11.23, which is best identified by a fluorescence in-situ hybridisation technique.
Aarskog syndrome
Short fingers with hyperextensible joints and excess webbing between the digits; facial appearance with tall, prominent forehead and upturned corners of the mouth; 'shawl' scrotum; lack of significant intellectual difficulties; X-linked pattern of inheritance.
Molecular genetic testing will identify mutations in FGD1 on the X chromosome.

Normal pressure hydrocephalus

Parkinson's disease
Asymmetric symptoms.Predominant tremor usually affecting face and arms.
Levodopa challenge test: symptoms respond to levodopa therapy.
Parkinson's-plus syndromes
Akinetic, rigid syndromes including multisystem atrophy sleep disorder, progressive supranuclear palsy, and corticobasal degeneration.Sometimes difficult to distinguish from normal pressure hydrocephalus (NPH), as clinical features are variable.Often affect top half of body (including speech and facial expressiveness) more severely.Multisystem atrophy: postural hypotension and impotence may be early features.Steele-Richardson-Olszewski syndrome: progressive supranuclear gaze palsy (i.e., difficulty directing gaze with preservation of reflex eye movements).Corticobasal degeneration: markedly asymmetric arm involvement.
CSF drainage procedure: unresponsive.
Cerebrovascular parkinsonism
Clinically indistinguishable from NPH.May represent the end result of untreated NPH when ischaemic damage to the brain is irreversible by CSF shunting.
CSF drainage procedure: unresponsive.
Alzheimer's dementia
Cognitive impairment generally precedes gait impairment.
CSF drainage procedure: unresponsive.
Other dementias
Cognitive impairment generally precedes gait impairment.
CSF drainage procedure: unresponsive.
Urinary outflow obstruction
Enlarged prostate.Urinary hesitancy.Poor urinary stream.
Urodynamic studies: demonstrate obstruction to urinary outflow.
Cervical myelopathy
Upper motor neuron signs in legs (e.g., brisk deep tendon reflexes and extensor plantar responses).
MRI cervical spine: demonstrates cervical myelopathy.

Obesity in adults

Hypothyroidism, primary
FatigueDepressionCold intoleranceExcessive sleepinessDry, coarse hairConstipationDry skinMuscle crampsDecreased concentration.
Free T4: lowTSH: elevated.
Hypothyroidism, central
FatigueDepressionCold intoleranceExcessive sleepinessDry, coarse hairConstipationDry skinMuscle crampsDecreased concentration.
Free T4: lowTSH: inappropriately low or normal.
Cushing's syndrome
Central obesityMoon faciesStriaeHirsutismLipodystrophyHypertensionDiabetesDepression.
Urinary free cortisol level: >50 micrograms/24 hoursLow-dose dexamethasone suppression test: morning serum cortisol >50 nanomol/L (>1.8 micrograms/dL)The presence of obesity may give false-positive results. If suspected, should be confirmed with further testing.

Obesity in children

Primary hypothyroidism
Fatigue.Attenuated growth.Cold intolerance.Constipation.Declining school performance.Dry skin.Coarse hair.Goitre.
Free T4 will be low for age.Thyrotropin (TSH) will be elevated for age.
Secondary hypothyroidism
Fatigue.Poor growth.Cold intolerance.Constipation.Dry skin.Coarse hair.
Free T4 will be low for age.Thyrotropin (TSH) will be low or normal for age.
Cushing's syndrome
Attenuated growth.Violaceous striae.Buffalo hump.Central adiposity.Moon facies.Hirsutism.Hypertension.Diabetes.
The 24-hour urinary free cortisol is elevated for age.
Prader-Willi syndrome
Short stature.Small hands and feet.Almond-shaped eyes.Picking on skin.Delayed puberty.Developmental delay.Hyperphagia.History of poor feeding and hypotonia as infant.
Genetic testing shows imprinting error on chromosome 15q.
Bardet-Biedl syndrome
Dysmorphic extremities.Retinitis pigmentosa.Developmental delay.Hypogonadism.Renal defects.
Mutations in several different genes have been linked to Bardet-Biedl syndrome. [38]
Pseudohypoparathyroidism
Short stature.Round face.Short metacarpals.Developmental delay.Basal ganglia calcification.
Serum calcium levels show hypocalcaemia.Serum phosphate levels show hyperphosphataemia.Serum PTH level is elevated.
Monogenic obesity
Severe, early-onset obesity.Usually associated with disruption of normal appetite control mechanisms.
Genetic testing identifies gene mutation in candidate genes such as leptin, ghrelin, adiponectin, peptide YY(3-36), and melanocortin 4 receptor (MC4-R). [39] [40]Mutations in MC4-R are the most common cause in children, occurring in approximately 5% of cases. [41]The obesity gene map database and the NIH and CDC database of association studies [National Institute on Aging. Genetic association database] can be used as a source of candidate genes.
Hypothalamic obesity
Severe obesity following treatment for intracranial lesions such as craniopharyngioma.Excessive appetite.
Abnormal hypothalamopituitary testing.
Obesity due to medication
Several classes of medication can be associated with weight gain, including neuropsychiatric medications and corticosteroids. [10]
Discontinuation of drug as a therapeutic trial.

Obsessive-compulsive disorder

Obsessive-compulsive personality disorder (OCPD)
More predominant among males; characterised by preoccupation with orderliness, details, rules, organisation, or schedules, to the degree that the point of the activity is lost.Perfectionism, hoarding, workaholism, and mental and interpersonal control at the expense of flexibility, openness, and efficiency.Absence of obsessions and compulsions in OCPD. May involve discomfort if things are sensed not to have been done completely. [43]The greater discomfort (alterations in anxiety or affect) associated with OCD seems to be the clinical factor that best distinguishes between the 2 disorders.Insight into behaviour or symptoms usually absent.
History is used to distinguish OCPD from OCD.Assessment of OCPD may be conducted through structured interviews for diagnosis such as the Structured Clinical Interview for DSM-II (SCID-II), the Diagnostic Interview for Personality Disorders (DIPD), and the Structured Interview for DSM-III Personality Disorders (SIDP). [44] [45]Clinically, the ego-dystonic nature of obsessions may also distinguish obsessions from the ego-syntonic traits of OCPD.
Body dysmorphic disorder (BDD)
Preoccupation with an imagined defect in appearance that is obsessive in nature.
Separate diagnosis of OCD should be made only when the obsessions or compulsions are not restricted to concerns about appearance. [31]
Hypochondriasis
Preoccupied with fears of having, or the idea that one has, a serious disease, based on a misinterpretation of bodily symptoms. [31]
History is used to distinguish hypochondriasis from OCD. As specified by the DSM-IV-TR, a separate diagnosis of OCD is given only when the obsessions or compulsions are not restricted to concerns about illness (e.g., checking locks). [31]
Delusional disorders
False belief that is firmly sustained and based on incorrect inference about reality; compulsions may be absent.
OCD can share features with delusional disorders, such as magic thinking; in fact, it has also been conceptualised by cognitive theories as a form of belief disorder similar to a delusion or an overvalued idea that is a product of distorted reasoning processes. [46]
Severe social phobia
Can mimic the anxiety related to obsessive-compulsive avoidance.
None
Panic disorder
Can mimic the anxiety related to obsessive-compulsive avoidance.
None
Autism
May have stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements). [31]Impaired social interaction, problems with verbal and non-verbal communication, and unusual, repetitive, compulsive behaviour or severely limited activities and interests.
None
Asperger's syndrome
May have stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements). [31]Poor social interactions, obsessions, odd speech patterns, and other peculiar mannerisms.Often have few facial expressions and have difficulty reading the body language of others.May engage in obsessive routines and may display an unusual sensitivity to sensory stimuli.Restrictive interests are also typical, but usually IQ is normal, or, in some cases, higher than normal.
None.

Obstructive sleep apnoea in adults

Central sleep apnoea and Cheyne-Stokes respiration (CSB)
Recurrent episodes of apnoea with absence of respiratory effort. [1]CSB associated with CHF, renal failure, or cerebrovascular disease, which is not necessarily present with OSA. [1]
Polysomnogram: in OSA there is evidence of thoraco-abdominal effort, whereas episodes of central apnoea are devoid of effort signal on thoraco-abdominal sensors. [1] In CSB, a crescendo-decrescendo change in breathing amplitude interspersed by episodes of central apnoea or hypopnoea would be seen.
Narcolepsy
Level of sleepiness in narcolepsy may be higher on the Epworth Sleep Scale. [Epworth Sleepiness Scale]Some patients with narcolepsy have cataplexy, hypnagogic hallucinations, and sleep paralysis. [1]
OSA needs to be excluded or evidenced to be sufficiently treated. After OSA is excluded using polysomnography, a multiple sleep latency test (MLST) may be performed to assess for narcolepsy. [1]
Insufficient sleep
May be difficult to differentiate clinically.
Sleep diary and/or actigraphy should be used. However, total sleep time may still be under- or overestimated. Polysomnography is performed to rule out OSA if there are additional risk factors. [1]
Inadequate sleep hygiene
Improper sleep schedule with frequent napping. Routine use of alcohol, nicotine, caffeine, and engaging in stimulating activities close to bedtime. Poor bedroom environment.
Diagnosis is usually clinical; however, actigraphy may be used to exclude OSA.
Periodic limb movement disorder
If restless leg syndrome is present, patients may describe an urge to move legs due to discomfort during periods of inactivity (usually in evening), which is relieved by motion. [1]
OSA is excluded by polysomnography or sufficiently treated to ascribe the excessive sleepiness to the limb movements on a polysomnogram. [1]
Hypersomnia due to drug or substance use
Difficult to differentiate clinically.
Urine or blood toxicological analysis may be performed for suspected substance. If the patient is no longer dependent on the drug and symptoms persist, a polysomnogram is performed.
Hypothyroidism
Patient may have cold intolerance, constipation, coarse hair, puffiness, and coarse skin.Although these symptoms are not exclusive to hypothyroidism, they are not associated with OSA in absence of hypothyroidism.
TSH and free T4 levels are measured. In patients with primary hypothyroidism, TSH will be elevated and T4 will be low.
Laryngospasm related to gastro-oesophageal reflux
May be associated with more exaggerated choking symptom.
Differentiated using polysomnography.
Sleep-related hypoventilation
Caused by neuromuscular or chest wall disorders, lower airway obstruction, pulmonary parenchymal or vascular pathology, or medullary lesions.May also coexist with OSA.
Differentiated using polysomnography and clinical criteria/diagnoses. Polysomnogram will show greater duration of oxygen desaturations.Patient will develop hypercapnia. [1]

Obstructive uropathy

Parapelvic cyst
Usually asymptomatic. May appear similar to hydronephrosis but there is no obstruction present.
If a radiologist cannot differentiate on ultrasound, a nuclear renography scan or CT scan with intravenous contrast can rule out obstruction.
Hydronephrosis of pregnancy
Hydronephrosis is found in 43% to 100% of pregnant women and tends to progress throughout gestation; most patients are clinically asymptomatic.
If a patient is asymptomatic, no further testing is indicated.Renal ultrasonography is indicated if a patient has flank pain, pyelonephritis, or renal failure. Hydronephrosis beyond the level of the pelvic brim is a sign that obstruction from another cause may be present.Magnetic resonance urography is an emerging technique to evaluate the level of obstruction.
Abdominal aortic aneurysm
Haemodynamic instability, personal or family history of abdominal aneurysm, bilateral loin pain; pulsatile mass in the abdomen.
CT abdomen/pelvis with contrast will demonstrate aneurysm sac and extravasation of contrast if leaking.
Appendicitis
Focal tenderness over McBurney's point. Patient often prefers to lie still to avoid pain on movement. Gradual onset of symptoms.
Diagnosis usually clinical.CT scan can identify an inflamed appendix.WBC and CRP often elevated.
Gynaecological disorders (e.g., ovarian torsion, cyst)
No haematuria; pain may be associated with menses.
Perform urine pregnancy test in all females of reproductive age before imaging.CT scan of the abdomen and pelvis may demonstrate ovarian pathology.Transvaginal ultrasound is first-choice investigation if a gynaecological cause is more likely than renal colic: may demonstrate ovarian torsion.
Ectopic pregnancy
May be haemodynamically unstable; unilateral abdominal pain more pronounced than loin pain; may have features of peritonitis (e.g., guarding and rebound tenderness).
Positive pregnancy test and gestation of about 6 weeks with ectopic pregnancy.Transvaginal ultrasound reveals ectopic pregnancy, dilatation of fallopian tube and free fluid if present.
Renal failure
No lower abdominal pain, no bladder distention; may be pruritic, have nausea or anorexia; may have other systemic illness or recent history of dehydration or fluid loss (e.g., post surgery).
Catheterisation: minimal urine.Urea and creatinine: elevated urea and creatinine.
Bowel obstruction
Bilious vomiting typically associated with small bowel obstruction; severe constipation; previous abdominal surgery or obstructed hernia present. May have concurrent dehydration and acute renal failure.
Abdominal x-ray may demonstrate dilated bowel loops.CT abdomen may show dilated loops of bowel and transition point if mechanical obstruction present.

Occupational asthma

Work-exacerbated asthma
Non-specific worsening of pre-existing or coincidental asthma due to workplace irritants such as dust and fumes, or common allergens that may be present in the workplace. [15] [35]Usually a history of preceding asthma before the job, which is associated with worsening asthma symptoms.
Negative specific inhalation challenge (when the correct agent is identified and the test is available) and lack of change in serial non-specific bronchial hyper-responsiveness (NSBHR) testing are suggestive of work-exacerbated asthma.However, lack of change in airway responsiveness away from the suspected work agent does not exclude OA. Advanced or long-standing sensitiser-induced OA may be associated with less temporal variability in symptoms and lung function with workplace exposures.
Occupational eosinophilic bronchitis
Bronchitis (chronic cough) worse at work may be present but without other manifestations of asthma (e.g., wheezing). [3]
Sputum eosinophilia (worse at work) in the absence of demonstrable variable airflow limitation or non-specific airway hyper-responsiveness. [36]
Coincidental non-occupational asthma
Asthma is a common condition that frequently will have an onset, or recurrence, in adult life. The clinician should take a history of the home environment to identify other potential allergens such as a cat or dust. Without the identification of features of irritant-induced OA, a workplace sensitiser, or objective evidence of worsening at the workplace to suggest sensitiser-induced OA, unrelated asthma should be considered. [15] [37]
Clinical diagnosis: lack of features to suggest irritant-induced OA or changes in symptoms, medication needs, pulmonary function, or bronchial hyper-responsiveness associated with workplace exposures that suggest sensitiser-induced OA make the presence of non-occupational asthma more likely.
Hypersensitivity pneumonitis
Many substances that cause OA may also cause hypersensitivity pneumonitis (HP), including diisocyanate exposure.In HP, wheezing tends not to be a prominent feature, and patients with the acute form may experience fevers and chills.
Absence of (or mild) NSBHROther pulmonary function abnormalities associated with HP include a restrictive ventilatory defect and impairment in gas transfer.Chest x-ray shows patchy, nodular infiltrates in acute and subacute HP; fibrosis in chronic HP.High-resolution CT chest in chronic HP shows ground-glass shadowing/attenuation and poorly defined micronodules. There is extensive honeycombing in late stages.
Chronic bronchitis/COPD
Dyspnoea may occur with or without wheezing, cough, or sputum. Examination may show barrel chest, hyper-resonance to percussion, and distant breath sounds.It is estimated that approximately 15% of COPD may be work-related from exposure to factors such as mineral and organic dusts. [38] COPD should especially be considered if there is a history of tobacco use and less day-to-day variability in symptoms.
Lack of significant variability in airflow obstruction and an absence of or only mild NSBRH (although COPD and asthma may co-exist).
Vocal cord dysfunction
Upper airway disorders are common asthma masqueraders. [39] Asthma may be present in addition to vocal cord dysfunction.
Pulmonary function testing may suggest extrathoracic airflow limitation as caused by paradoxical vocal cord movement by the presence of a flattened inspiratory flow volume loop. [40]Lack of objective airflow obstruction or NSBHR is supportive of the diagnosis; however, assessment by an otolaryngologist and speech therapist experienced in the field is recommended. [39]

Oesophageal cancer

Benign stricture
Usually associated with a long history of heartburn and slowly progressive dysphagia.
Oesophagogastroduodenoscopy (OGD) shows stricture of benign aetiology.
Achalasia
Long history of regurgitation with no history of heartburn. May be clinically indistinguishable from oesophageal cancer.
Upper GI series shows a typical 'bird's beak' filling defect.OGD has low sensitivity for the diagnosis of achalasia, and is often reported to be normal in early achalasia.Oesophageal manometry shows incomplete relaxation of the lower oesophageal sphincter.
Barrett's oesophagus
Long-standing reflux. Dysphagia rare.
OGD and biopsy will differentiate between benign intestinal metaplasia, dysplasia, and actual invasive cancer.

Oesophageal varices

Hiatal hernia
Commonly presents as heartburn and gastro-oesophageal reflux.
Endoscopy will show absence of varices.
Gastric varices
These patients may have evidence of chronic liver disease but may or may not have cirrhosis: for example, splenic vein thrombosis leads to isolated gastric varices.Patients who have oesophageal varices may also have gastric varices.
Endoscopy will show gastric varices but none in oesophagus. Often gastric varices are an extension of oesophageal varices, but isolated gastric varices can also be found.
Mallory-Weiss tear
Haematemesis is preceded by vomiting. Mallory-Weiss tear is more frequent in patients with history of alcohol abuse and therefore may be associated with chronic liver disease.
Endoscopy will show lacerations of oesophageal mucosa.
Peptic ulcer disease
Most commonly presents as heartburn. In active bleeding from an ulcer it may be difficult to distinguish from variceal bleeding.
Endoscopy will show peptic ulcer disease with ulcers in the stomach and/or duodenum.
Gastric antral vascular ectasia
Absence of signs of liver disease.
Endoscopy will show multiple erythematous mucosal linear streaks in the antrum.

Omphalocele and gastroschisis

Cloacal exstrophy
Rare midline defect of the lower abdominal wall in which intestine lie outside of the abdomen, often surrounded by two halves of the bladder. Genitalia are often bifurcated, the rectum may communicate with the bladder and an imperforate anus may be present.
Prenatal ultrasonography: visualisation of defect with the presence of gut or other abdominal viscera outside of the abdominal cavity.Postnatal physical exam: confirmatory of diagnosis.

Open-angle glaucoma

Low-tension glaucoma
Usually asymptomatic; this is a subset of open-angle glaucoma in which intra-ocular pressure is normal.
Intra-ocular pressure is normal.
Closed-angle glaucoma
Presents acutely with pain and redness; a poorly reactive, mid-dilated pupil; nausea and vomiting; a hazy cornea; and blurred vision.May have intermittent pain on entering a dark room. [1]
Gonioscopy reveals a closed angle.
High myopia
Although the cup-to-disc ratio may be large, no cup-to-disc enlargement is documented.Intra-ocular pressure is normal.Visual field defects do not change over time. [1]
Testing shows highly myopic refraction.
Ocular hypertension
Characterised by increased intra-ocular pressure in the absence of evidence of damage to the nerve fibre layer. [1]
Characterised by a normal visual field test and no enlargement of the cup-to-disc ratio over time.

Opiate overdose

Clonidine/imidazolines overdose
Presents with more profound bradycardia and hypotension than opiate overdose.
While patients may have a minor response to naloxone, most do not have a dramatic response.
Antipsychotic overdose
Presents with hypotension and tachycardia, but will not have the profound bradypnoea seen in opiate overdose.
No response to naloxone.
Pontine haemorrhage
Presents with miosis, but other features of opiate overdose, such as bradypnoea, will not be present.
No response to naloxone.
Ketamine overdose
CNS depression and miosis present in a minority of cases. Nystagmus is usually present and significant respiratory depression is absent, differentiating this from opiate overdose.
No response to naloxone.
Phencyclidine (PCP) overdose
CNS depression and miosis present in a minority of cases. Nystagmus is usually present and significant respiratory depression is absent.
No response to naloxone.
Alcohol intoxication
Usually only altered mental state present, without miosis and significant respiratory depression.
No response to naloxone; serum alcohol level will be positive.
Sedative hypnotic overdose
Miosis not present.
No response to naloxone.

Opioid use disorder

Alcohol intoxication
History of recent alcohol ingestion.Alcoholic breath and clinically significant maladaptive behavioural changes during or following alcohol ingestion.Lack of co-ordination and unsteady gait.Nystagmus.Impaired attention.Coma.
Urine toxicology negative for opioids.Blood alcohol levels give an indicator of the level of alcohol in the blood.
Sedative intoxication
History of recent sedative ingestion.Hostility or mood swings.Poor judgement.Inappropriate sexual behaviour.Lack of co-ordination.Inattention.Blackouts.Extreme sluggishness.Stupor.Coma.
Urine toxicology negative for opioids.Toxicology screen will show presence of the suspected drug in a blood or urine sample.
Anticholinergic intoxication
History of recent anticholinergic ingestion.Rapid onset of alteration in mood, cognition, and perception in the presence of a clear sensorium.Dry flushed skin.
Urine toxicology negative for opioids.If a specific anticholinergic agent is suspected, blood levels should be measured to confirm diagnosis.
Phencyclidine (PCP) intoxication
History of recent PCP use.Involuntary rapid movements of the eyes, vertically or horizontally.Palpitations.Drooling.Hyperthermia.Reduced response to pain.Increased alertness.Lack of muscle coordination.Disordered thinking or impaired judgement.Schizophrenic-like psychoses.Coma.Features of rhabdomyolysis (asymptomatic or present with generalized malaise or dark urine).
Urine toxicology negative for opioids.Toxicology screen will show presence of PCP in a blood or urine sample.Serum CK: more than 5 times normal if rhabdomyolysis is present.
Brain injury
History of brain injury.Altered sensorium.Neurological deficits may or may not be present.
Urine toxicology negative for opioids.Injury seen on MRI or CT brain.
Hepatic encephalopathy
Usually secondary to an underlying medical illness.Altered consciousness.Confusion secondary to hepatic dysfunction.
Urine toxicology negative for opioids.Elevated LFTs.
Uraemia
Usually a manifestation of underlying medical illness such as renal failure.Headache.Skin discoloration.Pruritus.
Urine toxicology negative for opioids.Fluid, electrolyte, and hormone imbalances, and metabolic abnormalities, will be present, which develop in parallel with deterioration of renal function.FBC, urinalysis, urine culture and colony count, serum and urine osmolality, chemistry panel, sedimentation rate, arterial blood gas analysis, blood volume, cystoscopy, and retrograde pyelography should be ordered.Additional studies include abdominal CT scan, ultrasonography, and renal biopsy.Results of these tests will be specific to the underlying medical illness causing uraemia.
Hypoglycaemia
Abnormal behaviour such as the inability to complete routine tasks.Visual disturbances.Palpitations.Tremors.Anxiety.Coma and seizures are uncommon.
Urine toxicology negative for opioids.Random serum blood glucose level <4.4 mmol/L (<80 mg/dL).
Diabetic ketoacidosis
Life-threatening condition secondary to diabetes mellitus.Sluggishness and extreme tiredness.Polydipsia and polyuria.Acetone breath.Hyperventilation.Agitation.
Urine toxicology negative for opioids.Serum glucose level usually >13.9 mmol/L (>250 mg/dL) (although it is usually much higher).Blood pH level <7.3.Serum bicarbonate level <18 mmol/L (<18 mEq/L).Elevated anion gap.
Alcohol or sedative withdrawal
Anxiety or irritability.Emotional volatility or agitation.Depression.Palpitations.Clammy skin.Tremors.Delirium tremens (a state of confusion and hallucinations).Convulsions.Blackouts.
Urine toxicology negative for opioids.Toxicology screen will show presence of the suspected sedative in a blood or urine sample.Blood alcohol levels give an indicator of the level of alcohol in the blood.Elevated LFTs.
Anxiety
Usually precipitated by high stress.Headache.Palpitations.
Urine toxicology negative for opioids.Clinical confirmation of diagnosis by a psychiatrist.
Depression
Decreased interest and loss of energy.Sadness.Feelings of guilt.Decreased concentration.Appetite changes.Psychomotor retardation or agitation.Suicidal intent/ideation.
Urine toxicology negative for opioids.Clinical confirmation of diagnosis by a psychiatrist.
Hyperthyroidism
Palpitations.Heat intolerance.Nervousness.Amenorrhoea.Fatigue.Tremors.Warm moist skin.Staring gaze.
Urine toxicology negative for opioids.Thyroid stimulating hormone (TSH) levels will be decreased along with increased T3 and T4 levels.Sometimes an iodine uptake scan is done to locate the cause of the hyperactive thyroid.
Phaeochromocytoma
Palpitations.Anxiety.Diaphoresis.Pallor.
Urine toxicology negative for opioids.Elevated serum or urine catecholamines and metanephrines.Neuroimaging (MRI or CT) helps to localise the tumour.Serum glucose level may be elevated.

Optic neuritis

Lyme disease
History of tick bite with characteristic rash of erythema migrans. There may also be musculoskeletal manifestations such as arthralgia and arthritis; neurological manifestations such as cranial nerve VII or other cranial nerve palsies, aseptic meningitis, radiculoneuropathy; cardiovascular complications such as AV block, myopericarditis.
ELISA or immunofluorescence assay, confirmed by a standardised Western blot assay.
Syphilis
History of primary syphilis, typically with a painless genital ulceration. Optic neuritis can occur in secondary or tertiary neurosyphilis.
Serological tests for syphilis.
HIV infection
History of HIV infection; complications and secondary infections may be present.
Serological tests for HIV.
Varicella-zoster
History of chickenpox; optic neuropathy is more likely to develop in patients who are immunocompromised.
Serological tests for varicella-zoster.
Aspergillosis
Generally seen in immunocompromised patients. May be otherwise asymptomtic, or may cause haemoptysis; weight loss, chronic cough, and malaise. Other systemic involvement may be present.
Serum Aspergillus galactomannan antigen by enzyme immunoassay positive in invasive disease; MRI or high-resolution CT of the brain may show focal lesions.
Cat-scratch disease
Typically presents with painful regional lymphadenopathy after a scratch from a cat (often a kitten), although an optic neuritis may be the only presenting feature.
Diagnosis has traditionally been clinical; indirect fluorescent antibody for Bartonella henselae may be positive.
SLE
Typically causes multi-system manifestations that may include constitutional, musculoskeletal, mucocutaneous, renal, gastrointestinal, cardiac, and pulmonary features as well as neurological symptoms and signs.
Positive antinuclear antibody.
Neuromyelitis optica (Devic's disease)
Visual symptoms accompanied by symptoms and signs attributable to spinal cord vasculitis (weakness, paralysis, sensory changes, bladder dysfunction).
Spinal cord MRI shows abnormalities in 3 or more consecutive spinal segments; brain MRI does not fulfil requirements for MS.
Sarcoidosis
Typically causes non-specific pulmonary symptoms of cough and breathlessness. May also produce constitutional symptoms, arthralgias, photophobia.
Diagnosis is confirmed by histology of affected organ showing non-caseating granulomas.
Behcet's syndrome
Recurrent mouth ulcers plus 2 other clinical manifestations (recurrent genital ulcers, skin lesions, eye lesions, or positive pathergy test). Other organs may also be involved. There may be a family history, and it is more common in people of Mediterranean, Middle Eastern, and East Asian origin.
No tests are specific for the disease.
Sjogren's syndrome
Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), caused by lymphocytic infiltration into the lacrimal and salivary glands. Can also be associated with dry skin, nose, throat, or vagina; arthralgias and myalgias; peripheral neuropathies; pulmonary, thyroid, and renal disorders; and lymphoma. Sometimes co-exists with autoimmune diseases (e.g., SLE, rheumatoid arthritis, systemic sclerosis).
Diagnosis is chiefly clinical; anti-Ro (SS-A) and anti-La (SS-B) may be positive, but are not so in every patient, and they may be positive in other conditions.
Giant cell arteritis
Most commonly seen in patients >50 years and typically accompanied by headache or jaw claudication.
ESR raised (≥50 mm/hour); temporal artery biopsy typically shows granulomatous inflammation, sometimes with multinucleated giant cells.
Takayas's arteritis
Most commonly seen in women in their 20s or 30s. Systemic symptoms may be present but headache and cranial symptoms are usually not. Patients often have absent or asymmetrical peripheral pulses and multiple arterial bruits.
Angiography, CT, or magnetic resonance angiography of the aorta and major arteries showing stenosis or occlusion.
Non-arteritic anterior ischaemic optic neuropathy
Typically a sudden onset of diminished vision in a hemifield in one eye, often on waking. Most patients have vascular risk factors. Pain is usually not a feature, and the patient is generally otherwise asymptomatic.
Diagnosis is usually by exclusion of arteritic causes of visual loss.
Drugs and toxins
Optic neuropathies caused by drugs or toxins need to be considered in patients receiving treatment with tamoxifen, ethambutol, tetracycline, quinine, amiodarone, and disulfiram. Other toxins include methyl alcohol, radiation, and lead. The time course is chronic (except for acute methanol intoxication), and pathology is non-inflammatory.
Funduscopy shows optic atrophy; MRI does not show enhancement of optic nerve.
Leber's hereditary optic neuropathy
A maternally inherited mitochondrial DNA disorder that affects primarily the optic nerves. Leber's hereditary optic neuropathy (LHON) can mimic ON. Visual loss is ultimately bilateral, either simultaneous at onset or sequential within 1 year. The temporal pattern of visual loss may be similar to ON, and visual acuity is often reduced to finger counting. Pain is seldom a feature of LHON. Occasionally there are associated subtle neurological abnormalities or white matter changes on MRI. Female carriers with a disease very similar to multiple sclerosis (MS) (with prominent binocular visual loss) have a LHON/MS overlap syndrome known as Harding's disease. [22]
Funduscopy acutely shows pseudo-oedema of the optic disc and peripapillary micro-angiopathy, which can be present in pre-symptomatic stages. More than 90% of familial cases are positive for primary LHON mutations affecting nucleotides 11778, 3460, or 14484 in mitochondrial genes involved in oxidative phosphorylation, a critical process in cellular energetics.

Oral candidiasis

Chemical burns
May be asymptomatic.May be a history of contact with chemical agent, most commonly from topical use of aspirin for toothache.White plaques cannot be scraped off.After elimination of the aetiological factor, lesions will resolve in 7 to 14 days.
Smear examination and periodic acid-Schiff staining will be negative for yeast forms or hyphae.
Reactive keratosis
Lesions are usually asymptomatic.May be able to identify a source of chronic irritation (e.g., a faulty dental restoration, an ill-fitting denture, or parafunctional habits such as bruxism or chronic cheek biting).
Definitive diagnosis is always through biopsy and histological evaluation of the lesion.
Hairy leukoplakia
Lesions are asymptomatic.
Definitive diagnosis is through biopsy and histological evaluation of the lesion.In situ hybridisation technique demonstrates the presence of EBV in the tissue.
Plaque-type lichen planus
Lesions are usually asymptomatic.There may be other lichenoid lesions in other areas of the skin.
Definitive diagnosis is through biopsy and histological evaluation of the lesion.Immunofluorescence staining of the tissue sample may provide additional evidence for the diagnosis, although it is infrequently performed.
Erosive lichen planus
Lesions are painful, but mostly when eating, whereas erythematous candidiasis may be associated with constant burning pain.Mucosal erosions and lichenoid lesions elsewhere on the skin may be present.
Definitive diagnosis is through biopsy and histological evaluation of the lesion and immunofluorescence staining of the tissue sample if additional diagnostic information is necessary.
Pre-malignant leukoplakia and carcinoma
Lesions are usually asymptomatic unless the expansion of malignancy encroaches on anatomical relationship between tissues.Regional lymph nodes may be enlarged.
Definitive diagnosis is through biopsy and histological evaluation of the lesion.Imaging techniques such as x-ray or CT are useful to determine local invasion of carcinoma.
Thermal burns
Lesions are usually painful but difficult to distinguish from erythematous candidiasis based on symptoms.Lesions are often local, and adequate history may indicate an incidence of burn with food.Lesions resolve in 7 to 14 days with no intervention.
No differentiating tests required.
Migratory glossitis
Lesions are usually asymptomatic.In patients who do complain of discomfort, burning is associated with eating spicy or sour food or alcohol-containing liquids, whereas symptomatic erythematous candidiasis is associated with constant burning.Atrophic zones of migratory glossitis are commonly patchy and are usually surrounded by elevated hyperkeratotic margins.
In the absence of clinically distinguishable features, histological examination of the tissue may be necessary.

Oral leukoplakia

Oral squamous cell carcinoma
May be associated lymphadenopathy, dysphagia.
Incisional biopsy and pathology demonstrates evidence of invasive carcinoma; keratin pearls may be seen.
Chronic candidiasis
The tissue response to chronic candidal infection is hyperplastic in nature - in particular, in the retrocommissural area, where a more speckled to atrophic surface pattern is often present. View imageIn the immunosuppressed patient and in cases of T-cell dysfunction this finding assumes greater clinical importance, as it concerns potential malignant transformation within the speckled areas.
Candidal smear is positive.Incisional biopsy and pathology may demonstrate a range of features, from a benign hyperplasia with hyperkeratosis in most circumstances, to variable degrees of dysplasia or invasive cancer less frequently. Surface Candida may be seen.
Submucosal fibrosis
Underlying tissues are firm and inelastic.
Incisional biopsy and pathology will demonstrate epithelial atrophy and fibrosis of the underlying lamina propria.
Hairy leukoplakia
Painless white plaques along the lateral tongue borders. View imageHistory of HIV or immunosuppression.
Definitive diagnosis is through biopsy and histological evaluation of the lesion.In situ hybridisation technique demonstrates the presence of EBV in the tissue.
Syphilitic leukoplakia
Typically located predominantly over the dorsum of the tongue, in contrast to the lateral and ventral surfaces, where the vast majority of oral leukoplakia are found; plaques of keratinised tissue with fissured topography are characteristic. [112]
Treponemal-specific serology tests are antigen-based tests and remain positive lifelong if current or past infection: tests include treponemal enzyme immune assay, Treponema pallidum particle agglutination, T pallidum haemaglutination, fluorescent antibody absorption tests, and immunocapture assay.Non-treponemal titres VDRL or RPR correlate with disease activity, decreasing or becoming non-reactive with effective treatment.
Frictional keratosis
May be able to identify a source of chronic irritation (e.g., a faulty dental restoration, an ill-fitting denture, or parafunctional habits such as bruxism or chronic cheek biting).Removal of offending trauma may lead to resolution of keratosis.
Definitive diagnosis is through biopsy and histological evaluation of the lesion.
Lichen planus
Typically presents with reticular, atrophic, and erosive mucosal changes in a symmetrical distribution. Reticular/plaque lesions are usually asymptomatic; erosive lesions may be painful.Lichenoid lesions elsewhere on the skin may be present.
Incisional biopsy and pathology may demonstrate characteristic superficial keratinisation, dense banded lymphocytic infiltrate within the superficial lamina propria, and liquefactive basal layer degeneration and scattered colloid bodies or apoptotic keratinocytes.Epithelial dysplasia may be a feature. Malignant transformation is well recognised; the atrophic and erosive forms are reported to have the highest rate of malignant transformation, with published rates of malignant transformation of oral lichen planus ranging from 0% to 5.3%. [113]
Discoid lupus erythematosus
Typically presents with a lichenoid pattern of keratosis and erosive/inflammatory lesions. Most often the lesions are accompanied by radiating reticular striaform lesions; plaque-like lesions may also be seen but are less common. [114]However, in some cases, oral lesions with plaque-like configuration similar to leukoplakia may be evident in spite of quiescent disease elsewhere. [115]
ANA and antidouble-stranded DNA antibody positive.Incisional biopsy and pathology may demonstrate vacuolated keratinocytes, patchy periodic acid-Schiff-positive patches and oedema in the lamina propria, and severe or perivascular inflammatory infiltration. [116] Direct immunofluorescence will show an uneven globular deposition of IgG, IgA, and fibrinogen along the basement membrane zone. [117]
White sponge naevus
Rare inherited (autosomal dominant) developmental abnormality characterised by white plaques present on the buccal mucosa (often bilateral), and, less commonly, the lingual and labial tissues; vagina, rectum, and nasal cavity may also be affected.
No differentiating test is usually performed as clinical findings alone are usually adequate.

Oral mucositis

Oral candidiasis
Pseudomembranous oral candidiasis appears as white, curd-like plaques on the oral mucosa that can be removed with pressure, revealing an inflamed mucosa.Erythematous oral candidiasis appears as red, inflamed areas on the oral mucosa that may cause low-grade pain and burning, and mimic mild (non-ulcerated) mucositis.
Superficial smear of lesion for microscopy and/or fungal culture is positive.Secondary fungal infection, usually caused by C albicans, but also other candidal species (C glabrata and C tropicalis) is common in patients receiving head and neck irradiation, especially those with significant salivary compromise. [24] However, it should be noted that a positive smear or fungal culture does not exclude oral mucositis, because Candida infection can coexist with oral mucositis.
Herpes simplex virus infection
Recurrent herpes simplex virus (HSV) lesions typically present on the outer lip as 'cold sores,' but may present intra-orally, especially in patients undergoing myeloablative therapies (e.g., haematopoietic stem cell transplantation [HSCT] with total body irradiation).Intra-oral HSV begins as multiple 1- to 3-mm vesicles that lead to macular ulcers, most typically seen on keratinised mucosa such as the hard palate and gingiva.
Viral culture or PCR of vesicular lesions will be positive for HSV infection.However, it should be noted that a positive viral culture does not exclude oral mucositis because reactivation of HSV infection can coexist with oral mucositis.
Graft-versus-host disease
Acute graft-versus-host disease (GVHD) classically targets the skin, liver, and GI tract; chronic GVHD can involve almost any organ.Typically presents with an erythematous maculopapular rash, with intense pruritus; isolated oral GVHD is uncommon.
Liver function tests may show elevated transaminases, alkaline phosphatase, and/or bilirubin.In isolated oral GVHD, a mucosal biopsy reveals pathognomonic features (apoptosis at the base of epidermal rete pegs; perivascular lymphocytic infiltration in the dermis).

Orbital fractures

soft tissue trauma only
In cases in which surgical intervention is not urgently required, clinical review after traumatic oedema has resolved may reveal the cause of diplopia to be oedema alone.
No evidence of fractures at any stage of follow-up examinations, or on imaging.

Organophosphate poisoning

Carbamate poisoning
Essentially indistinguishable clinically from organophosphate poisoning, as some carbamate pesticides are anticholinesterases.A more rapid onset and resolution suggest this diagnosis.
There are no clinical differentiating tests.
Chlorphenoxy herbicide poisoning
Chest signs, pinpoint pupils, and increased secretions are not expected.
Cholinesterase activity is expected to be normal.Rhabdomyolysis is common in severe poisoning.
Opioid overdose
Excessive secretions are minimal and fasciculations will not be seen.
Rapid response to naloxone confirms diagnosis in most cases unless there is hypoxic brain damage.Cholinesterase activity is expected to be normal.
Brainstem stroke
Grossly excessive secretions are not seen.
Response to atropine and cholinesterase activity is expected to be normal.Imaging of head may detect stroke; however, images may appear normal early on.

Oropharyngeal cancer

Tonsillitis
Typical features include sore throat, painful swallowing, headache, fever, chills, red swollen tonsils with white patches, and enlarged tender cervical lymphadenopathy.Signs and symptoms resolve with antibiotics.
Throat culture may be positive.
Aphthous ulcer
Round, yellowish, elevated spot surrounded by a halo, followed by ulcer covered by white or greyish membrane surrounded by normal tissue.Absence of induration noted, and ulcer is self-limiting.
Clinical diagnosis.
Oral syphilis
Solitary deep-base ulceration with irregular-based border associated with cervical adenopathy; hx of oral sex.Resolves with antibiotics.
Positive VDRL test.
Oral tuberculosis
Single or multiple ulceration, with or without cervical adenopathy in HIV-positive patient.Resolves with anti-tuberculous and antiviral therapy.
Granulomatous lesions and acid-fast bacilli on biopsy.
Oral herpes simplex virus
Multiple blisters on an erythaematous base followed by painful ulceration; hx of oral sex.Resolves with acyclovir.
Tzanck smear for intranuclear inclusions (virus colonies).Culture of the blister positive for herpes simplex.
Oral cytomegalovirus infection
Painful, punched-out ulcerations with non-indurated border in HIV-positive patient.Resolves with ganciclovir.
Viral nuclear inclusion by histology, viral culture of tissue.
Non-Hodgkin's lymphoma
Mass involving Waldeyer's ring.
Excision biopsy of nodal tissue showing abnormal lymphocytes.Immunophenotype analysis and flow cytometric analysis of surface markers.

Orthostatic hypotension

Neurally mediated (vasovagal) syncope
Premonitory symptoms such as sweating and nausea are typical of neurally mediated (vasovagal) syncope, but do not occur in patients with chronic autonomic failure.Symptoms of neurally mediated syncope are intermittent and frequently occur with specific triggers (e.g., blood drawing, prolonged standing). In between episodes, blood pressure responses are normal, and symptoms are not related to standing, eating, or physical exercise.
In the tilt-table test, the blood pressure is initially maintained until, after a variable period, it falls abruptly, often in association with a drop in heart rate. In contrast, in orthostatic hypotension the fall in blood pressure occurs immediately upon head-up tilt, and is usually progressive.The autonomic response to the Valsalva manoeuvre is normal; in contrast, in autonomic failure there is lack of blood pressure overshoot after release of the strain.
Vertigo
Vertigo is the result of vestibular or cerebellar pathology, but it may be confused with the dizziness or light-headedness of orthostatic hypotension.
Neurological examination reveals cerebellar ataxia or nystagmus. Vestibular testing with electronystagmography shows abnormal responses.
Non-specific falls in older people
Gait imbalance and falls are common in older people and may be the result of impaired postural reflexes, reduced visual acuity, or orthopaedic problems, and may be confused with orthostatic hypotension. These can be assessed by physical examination, including a full neurological examination.
Neurological examination showing gait imbalance or abnormal postural reflexes.
Psychogenic syncope (pseudo-syncope)
Periods of unresponsiveness due to psychiatric disorders can easily be confused with syncope. A psychiatric evaluation is required to determine the cause.
There are no distinguishing tests.

Osgood-Schlatter's disease

Fracture of the tibial tubercle
Onset of symptoms is typically sudden and associated with a traumatic event. Patients are unable to actively extend the knee and may be unable to bear weight. [1]
X-rays demonstrate irregular fracture line, usually without fragmentation of the tubercle (such as may be seen in cases of OSD). May be associated with physeal arrest of the tibial tubercle leading to recurvatum deformity. [4]
Fat pad hypertrophy/impingement (Hoffa's disease)
Maximal tenderness is at the anterior joint line, typically lateral to the patellar tendon, not at the tibial tubercle. [1]
Plain x-rays are usually normal in Hoffa's disease, while knees with OSD may show fragmentation/enlargement at the tibial tubercle. [1]
Inferior patellar pole traction apophysitis (Sinding-Larsen and Johansson syndrome)
Maximal tenderness is at the inferior pole of the patella, not at the tibial tubercle. [1]
Plain x-rays will sometimes demonstrate a separated ossicle or elongation at the inferior pole of the patella, with normal appearance of the tibial tubercle, unlike in many cases of OSD. [1] [4]
Patellar stress fracture
A very rare entity.Patients may present with variable ability to bear weight, as well as pain, swelling, and localised tenderness over the anterior aspect of the patella (as opposed to the tenderness over the tibial tubercle in OSD).Patients may report a sensation of crack or pop with activities.
Plain x-rays may show a transverse fracture line, usually at the junction of the middle and distal thirds of the patella. Callus formation may also be noted, indicating reparative process at the site of injury. Typical findings of enlarged or fragmented tibial tubercle are absent.
Osteochondritis dissecans (OCD) of the knee
Patients typically present complaining of anterior or anteromedial knee pain, and intermittent knee swelling, sometimes accompanied by mechanical symptoms.A history of minor trauma may precede the onset of symptoms, or the condition may be completely atraumatic.Typically, tenderness is localised to the joint line (usually medial), with absence of tenderness at the tibial tubercle.
Classic location for OCD of the knee is the lateral aspect of the medial femoral condyle. The lesion may be visible on plain x-rays or may require MRI for diagnosis. [4]
Infrapatellar bursitis
Clinically may be difficult to differentiate from early OSD.Location of pain is similarly at or near patellar tendon insertion, although distinct tenderness to palpation over the tibial tubercle is usually absent.
X-rays are typically normal or demonstrate increased soft-tissue swelling in the infrapatellar region.MRI shows normal tibial tubercle and fluid accumulation in the infrapatellar region.
Patellar tendonitis
May be difficult to distinguish from early OSD, and may occur as secondary pathology in knees with OSD.
X-rays are typically normal or demonstrate increased soft-tissue swelling in the infrapatellar region.MRI shows normal tibial tubercle and may demonstrate increased signal in the patellar tendon on T2-weighted images.
Osteoid osteoma
Lesions of bone will often manifest as pain that occurs both at rest and with activity.Night-time pain may be present.
Plain x-rays identify a circular defect.
Osteosarcoma
Lesions of bone will often manifest as pain that occurs both at rest and with activity.Presents with systemic symptoms and signs such as fever, night sweats, and weight loss.
Plain x-rays demonstrate radiolucent lesion with areas of mottled radiodensity and ill-defined margins.CT or MRI is confirmatory.Bone biopsy performed by an experienced orthopaedic oncologist may be done to confirm the diagnosis.
Osteomyelitis
Lesions of bone will often manifest as pain that occurs both at rest and with activity.Presents with systemic symptoms and signs such as fever and chills.
Laboratory markers such as ESR, C-reactive protein, and WBC count may be elevated.Positive blood cultures for inciting organism.The earliest changes seen on plain x-rays are soft-tissue swelling, peri-osteal thickening, and focal osteopenia.MRI is confirmatory.
Slipped capital femoral epiphysis
Patients with disorders of the hip may present with referred knee pain (via the posterior branch of the obturator nerve), typically on the medial aspect of the knee.They may sometimes be unable to bear weight on the affected extremity and have a limp.Physical examination of such patients often demonstrates limited range of motion of the ipsilateral hip, with a relatively normal range of motion of the knee.An episode of minor trauma may precede this presentation.
X-rays of the hip and pelvis, including anteroposterior and frog-leg lateral views, demonstrate abnormality of the hip joint.X-rays of the knee are usually normal.

Osteoarthritis

Bursitis
Greater trochanteric bursitis in the hip and pes anserine bursitis in the knee present with pain over the lateral aspect of the hip and over the medial aspect of the knee, respectively. There is also local tenderness in these areas that is usually absent in simple OA.
Local anaesthetic and corticosteroid injection might be therapeutic and diagnostic if it relieves symptoms to a significant degree.
Gout
The onset of arthritis in gout is usually more acute and over a period of a few hours, but could mimic an exacerbation of acute OA.Gout or pseudogout often co-exists in the same joint. In acute attacks of crystal arthritis, the affected joint is usually red, hot, and acutely tender.Gout commonly involves the foot, especially the first metatarsophalangeal (MTP) joint, although it may affect almost any joint.
Arthrocentesis and joint fluid analysis, which shows leukocytes >2000 cells/mm^3, and the presence of sodium monourate crystals.
Pseudogout
The onset of arthritis in pseudogout (calcium pyrophosphate deposition [CPPD]) is usually more acute and over a period of a few hours, but could mimic an exacerbation of acute OA. Associated with other conditions (e.g., haemochromatosis) and results in secondary pseudo-OA, which often involves the MCP joints.Gout or pseudogout often co-exists in the same joint. In acute attacks of crystal arthritis, the affected joint is usually red, hot, and acutely tender.Pseudogout often involves the wrist and knee, although it may affect almost any joint.
Arthrocentesis and joint fluid analysis, which shows leukocytes >2000 cells/mm^3, and the presence of pyrophosphate crystals.Radiographs: chondrocalcinosis; in cases of haemochromatosis, hook-like osteophytes in the second and third metacarpal heads.
Rheumatoid arthritis (RA)
It is usually straightforward to differentiate RA from OA based on the number and distribution of the involved joints.RA usually causes a symmetrical small joint polyarthritis in the hands, particularly affecting the MCP joints and sparing the DIP joints. Typically, RA is associated with more prolonged morning stiffness than OA. Patients with acute RA may also feel generally unwell, with fatigue and low mood.Differentiation is sometimes challenging for hand involvement, and the two conditions, OA and RA , can co-exist.
In RA, ESR and CRP are abnormal and rheumatoid factor and anti-cyclic citrullinated antibodies are positive. Typical RA erosive changes are seen on x-ray, MRI, or ultrasound.
Psoriatic arthritis
Psoriatic arthritis can occur in the absence of skin psoriasis and often affects the DIP joints.In psoriatic arthritis, the joint involvement is usually asymmetrical, but inflammatory OA can be difficult to distinguish from some cases of psoriatic arthritis with only DIP involvement.
In psoriatic arthritis, x-ray shows typical erosive changes.
Avascular necrosis (AVN)
This is common in the hip and knee joints. The onset is subacute and there is usually a risk factor such as corticosteroid use. Early on, the joint examination is unremarkable, except for possible localised bony tenderness in the knee.
MRI is the most sensitive test in AVN. In the early stages, localised subchondral oedema is characteristic. In 50% of all cases, accompanying joint effusion may be found. Due to necrosis of the cells of bone marrow and bone fibrovascular tissue, reactions with hyperaemia can be delineated. [33]
Internal derangements (e.g., meniscal tears)
The onset of meniscal tears is usually acute and debilitating, with preceding trauma, although the trauma can be minor. Patients may describe true locking (normal flexion, but an inability to extend the affected knee).
MRI is sensitive in detecting both acute meniscal and cruciate ligament tears, although degenerative meniscal tears are common in OA.

Osteochondritis dissecans

Osteochondral fracture
Acute onset of pain following a traumatic event. May be associated with a large haemarthrosis.
Aspiration of the knee will demonstrate the presence of a haemarthrosis. X-rays or other advanced imaging including CT scan or MRI may demonstrate the osteochondral fragment.
Meniscal tear
May or may not be associated with traumatic event. Point of maximal tenderness will be along the joint line as opposed to femoral condyle. Pain with deep knee flexion will be posterior as opposed to pain in osteochondritis dissecans, which will move anteriorly with deep flexion.
X-rays will be normal with no evidence of osteochondritis dissecans. MRI may demonstrate the presence of a meniscal tear.
Septic arthritis
Effusion and synovitis will be present. May be associated with systemic signs of infection, including fever or chills. The joint may appear erythematous with increased warmth. Range of motion will be severely limited secondary to pain.
X-rays may appear normal with acute infection. FBC, ESR, and CRP should be ordered if possibility of infection exists. Aspiration with synovial fluid analysis for cell count, crystals, culture, and glucose level should be performed to rule out infection if infection remains a possibility.
Bone contusion
Joint pain following traumatic injury. Presence of effusion is unlikely. Close examination will reveal the point of maximal tenderness is over the bone as opposed to the articular surface. Mechanical symptoms will not be present.
X-ray examination will be normal. MRI will demonstrate the bone contusion with oedema in the region of injury.
Soft tissue contusion
Pain will be superficial. No effusion present. No mechanical symptoms. Tenderness will not be in the region of the articular surface, but in the overlying soft tissue.
Radiographs will be normal. MRI, if ordered, will demonstrate oedema in the soft tissue overlying the joint.
Panner's disease
Impaired blood supply to capitellum growth plate. Occurs in children between the ages of 5 and 12 years.
X-rays show radiolucency of the subarticular surfaces.

Osteomalacia

Osteoporosis
Both osteoporosis and osteomalacia may present with bone fractures. Typically, osteoporosis is painless and insidious until a fracture develops. Characteristically, osteomalacia is a painful bone disorder at onset.Osteomalacia patients report a history of limited sunlight exposure, sunscreen use, malabsorption, anticonvulsant use, or renal failure. Osteoporosis typically occurs with advancing age.
Osteoporosis typically presents with normal serum calcium, phosphorus, alkaline phosphatase, vitamin D, and PTH levels. In contrast, osteomalacia is characterised by hypophosphataemia, hypocalcaemia, increased alkaline phosphatase levels, low levels of vitamin D metabolites, and secondary hyperparathyroidism.Urinary calcium levels may be normal in osteoporosis but are low in osteomalacia. Both conditions appear as low bone mass on radiological studies and DXA scan. However, specific radiological findings unique to osteomalacia include Looser pseudofractures.A bone biopsy is the best differentiating test. [36]On x-ray, the coarseness of the trabeculae in osteomalacia may differentiate the 2 diagnoses.
Paget's disease
Most patients with Paget's disease are asymptomatic. In contrast, patients with osteomalacia have bony tenderness and pain.
Normal serum calcium and a markedly elevated serum alkaline phosphatase are seen in Paget's disease. On x-ray, gross deformities of bone may be seen, characteristic of Paget's disease, such as enlargement of the skull and bowing of the femur or tibia.

Osteomyelitis

Metastatic bone cancer or osteosarcoma
History of bone cancer, systemic symptoms (e.g., weight loss), a known primary lesion, and/or bone pain.
X-rays of area of suspected infection would not demonstrate darkened areas typical of osteomyelitis. Conventional features of osteosarcoma are destruction of normal trabecular bone pattern, a mixture of radiodense and radiolucent areas, periosteal new bone formation, and formation of Codman's triangle (triangular elevation of periosteum). If no abnormalities are visible on plain radiographs, MRI of the entire length of involved bone is indicated. [63] [64]Cultures examined through 1 or more commonly used methods of testing would confirm the absence of a bacterial pathogen. This determination is usually made pre-operatively; in some cases; however, a final diagnosis may only be made definitively through exploratory surgery.Bone biopsy may sometimes be indicated to confirm the diagnosis of metastatic disease by cytological analysis. [65]
Old or new trauma
History of trauma and absence of fever, erythema, and/or inflammation.
Cultures examined through 1 or more commonly used methods of testing would confirm the absence of a bacterial pathogen.X-ray findings suggestive of trauma.
Non-infected non-union
History of fracture and absence of fever, erythema, and/or inflammation.
Radiographical changes in non-infected traumatic bone are difficult to differentiate from infected bone because of distortion of bone architecture after fractures or multiple surgeries. [66]If plain radiographs are inconclusive, MRI will provide a more detailed image of bone inflammation and soft tissue damage than CT or radionuclide scanning. MRI cannot be performed in patients with metallic implants, limiting its usefulness in suspected post-traumatic infections.
Aseptic loosening of hardware
Absence of fever, erythema, and/or inflammation.
Differentiating infection from aseptic loosening is difficult because both are similar at clinical and histopathological examination.Radiolucent areas in x-rays will indicate loosening of orthopaedic hardware that may result in pain, swelling, and other symptoms.Cultures will confirm whether an infection is present.Radionuclide scan at suspected infection site can be useful in ruling out infection, but is complicated by variations in prosthetics.

Osteoporosis

Multiple myeloma
Bone pain and symptoms of anaemia and renal failure.
Urine electrophoresis reveals Bence Jones proteinuria; serum electrophoresis reveals monoclonal gammopathy.
Osteomalacia
Difficult to differentiate clinically.
PTH levels elevated; bone biopsy standard for confirmation of poor mineralisation.
Chronic kidney disease-bone and mineral disorder
Difficult to differentiate clinically. May have known history of renal failure. May present with bone pain and diminished muscular strength.
Serum creatinine and PTH elevated.
Primary hyperparathyroidism
May be signs of hypercalcaemia, including anorexia, nausea, constipation, and abdominal pain.Often asymptomatic.
Serum PTH elevated.
Metastatic bone malignancy
May have known history of cancer.Symptoms of bone pain after minor injury may be the same as in cases of osteoporosis, but may also occur in atypical locations.
DXA may be normal.CT may show presence of tumour.Bone scan shows multiple hot spots.Definitive test is bone biopsy and appropriate investigations to determine primary.
Vertebral deformities
Difficult to differentiate clinically.
Spinal deformities such as osteoarthritis and scoliosis may be mistaken for osteoporotic vertebral fractures. [3]X-ray and further imaging may be required for diagnosis.

Osteoporotic spinal compression fractures

Muscular pain
In contrast with spinal compression fractures, focal kyphosis and height reduction are absent in muscular pain. Localised bony tenderness, which characterises the acute stage of a fracture, is also absent.
Imaging tests exclude underlying fracture.
Spinal stenosis
Spinal claudication (pain in the buttock, thigh, or calf) is the classic symptom of central canal stenosis. It is more common in older patients. Pain and numbness usually occurs in 1 or both legs on walking and is relieved by spinal flexion, so that patients report less pain when sitting or leaning on a grocery cart.
MRI and/or CT can confirm central canal stenosis and may indicate other causes of low back pain.
Pathological fracture
Differentiating pathological fractures from osteoporotic fractures can be difficult on the basis of clinical features alone.There may be other local or systemic signs and symptoms related to the primary tumour if malignancy is present.
Pathological fractures may be caused by tumour infiltration (e.g., multiple myeloma, metastatic disease) or other metabolic disease (e.g., osteomalacia).A bone profile is useful to determine a metabolic cause. This includes serum calcium, albumin, parathyroid hormone, phosphate, ALP, magnesium, creatinine; plasma PTH, serum 25OHD and 125DOHD, and plasma TmP GFR.MRI and CT may identify tumour pathology. Presence of a soft-tissue mass or signal change extending into the pedicle strongly suggests tumour. [34] Blastic metastases appear hypodense on T1- and T2-weighted MRI images; lytic metastases are enhanced diffusely with contrast medium. [35]Bone scans may also show metastatic disease by revealing multiple foci of increased radionuclide uptake.
Referred pain
Pain may be referred to the back from visceral disease, such as aortic aneurysm, gastrointestinal disease, renal problems, and pelvic disease (prostatitis and pelvic inflammatory disease).
Physical examination, ultrasonography, and CT/MRI confirm the diagnosis. Aortic aneurysm should be suspected among older patients with coronary artery disease or multiple risk factors.

OSTEOSARCOMA

Ewing's sarcoma
Same age range and predilection for males.Type II symptoms (e.g., fever, night sweats) are usually seen.
Conventional radiographs show a metaphyseal or diaphyseal tumour with a predominantly lytic appearance. No bone matrix is radiographically identified.MRI shows a large soft tissue mass.Biopsy shows a small blue cell tumour with no osteoid production and represents the confirmatory test.Cytogenetic and/or molecular studies show the typical translocations/molecular aberrations of Ewing sarcoma family of tumours and help rule out small cell osteosarcoma (a rare sub-type of osteosarcoma with very little osteoid production).
Chondrosarcoma
Most common in patients between 50 and 60 years of age.The tumour has a predilection for the pelvic bones and a slower growth rate.The main symptom is severe pain that is not relieved by rest and is worse at night.
Conventional radiographs show a lytic lesion centred in the long bone metaphysis, with a permeative growth pattern scalloping the cortex and showing intra-tumoural calcifications, with a flocculent or ring-shaped appearance. The cortex is usually thickened with a slightly expanded and fusiform appearance, mainly due to the slow permeative growth of the tumour (chronic periosteal reaction). Scalloping of the inner cortex is a radiographic sign worrisome for malignancy.Biopsy is the confirmatory test.
Malignant fibrous histiocytoma
Most common in older patients.Frequently presents with pathological fracture.
Conventional radiographs show purely osteolytic tumour with minimal periosteal reaction.Biopsy shows a typical spindle cell pleomorphic sarcoma with storiform architecture.
Giant cell tumour of bone
Most common in skeletally mature women.Usually presents with bone pain and sometimes pathological fractures.
Conventional radiographs show tumour with an osteolytic appearance located in the epiphysis of long bones, with the distal femur and proximal tibia being the most commonly affected. Although benign, the tumour is locally aggressive. This translates radiographically into the absence of an osteosclerotic rim at its periphery as well as the presence of a soft tissue mass. No bone/osteoid formation is identified.Biopsy shows typical appearance of evenly distributed giant cells in a mononuclear stroma. The nuclei of the giant cells resemble the nuclei of the mononuclear stromal cells.
Metastases from other malignancies
Generally occur in older age group than osteosarcoma.Usual history of a primary malignancy known to metastasise to bone, such as breast, lung, thyroid, kidney, and prostate.
Conventional radiographs and radionuclide scans usually show osteolytic lesions (rarely osteoblastic) involving multiple bones.CT imaging may reveal other organs affected by metastatic disease.Biopsy usually confirms the diagnosis.
Lymphoma
More common in older men.Rare as a primary bone neoplasm. Type II general symptoms (e.g., fever, night sweats) and weight loss are common.
Conventional radiographs may be normal (tumour cells tend to grow between patient's bony trabeculae with little bone destruction). There may be multiple or single bone involvement.MRI shows focal change in the marrow signal.Bone marrow biopsy is usually the confirmatory test.Flow cytometric studies should be considered in patients suspected of having lymphoma.
Osteomyelitis
Primary (haematogenous) osteomyelitis is associated with fever, local swelling, and fistula formation.A history of recent trauma with open fracture is significant for secondary osteomyelitis.
C-reactive protein and ESR are markedly elevated.Biopsy shows necrotic bone, fibrotic marrow, and chronic inflammation with or without an acute inflammatory component.Reactive bone is usually produced as part of an associated periosteal reaction.
Langerhans' cell histiocytosis
Tends to have wide age distribution. However, 60% of cases arise in patients younger than 10 years of age.Localised and systemic forms of the disease exist. Has a predilection for the bones of the skull, especially the calvarium, but any other bone can be involved.Local pain and swelling are common.
ESR elevated.Radiographically there are multiple lytic lesions with significant periosteal reaction.Biopsy shows a proliferation of neoplastic Langerhans' cells in an inflammatory background.
Osteoblastoma
Benign osteoid-producing tumour with roughly same age and sex distribution as osteosarcoma.Pain of long duration is the most common presenting symptom.For lesions located in the spine, scoliosis and neurological symptoms may occur.
Conventional radiography reveals a radiolucent lesion in a long bone metaphysis or posterior arch of a vertebra, with a central area of radiodensity secondary to osteoid and bone production. No soft tissue mass is associated with the bone lesion.Biopsy shows osteoid and woven bone rimmed by osteoblasts in a fibrovascular stroma.
Aneurysmal bone cyst
Same age range and location as osteosarcoma.Presents with pain and occasional pathological fracture. Secondary aneurysmal bone cysts can be seen in older patients, superimposed on other primary neoplasms.
Conventional radiographs show radiolucent expansile bone lesion.MRI shows fluid levels on T2-weighted images.Biopsy can differentiate from telangiectatic osteosarcoma, which displays obvious histological features of malignancy (marked cellular pleomorphism, high and abnormal mitotic activity).
Fibrous dysplasia
The presentation of polyostotic fibrous dysplasia commonly includes bone deformity and pathological fracture.Wide age range at presentation and no gender preference.
Conventional radiographs show ground glass appearance with no associated soft tissue mass. There are generally no aggressive radiographical features. Pathological fracture may be seen.

OSTEOSARCOMA High Risk

Ewing's sarcoma
Same age range and predilection for males.Type II symptoms (e.g., fever, night sweats) are usually seen.
Conventional radiographs show a metaphyseal or diaphyseal tumour with a predominantly lytic appearance. No bone matrix is radiographically identified.MRI shows a large soft tissue mass.Biopsy shows a small blue cell tumour with no osteoid production and represents the confirmatory test.Cytogenetic and/or molecular studies show the typical translocations/molecular aberrations of Ewing sarcoma family of tumours and help rule out small cell osteosarcoma (a rare sub-type of osteosarcoma with very little osteoid production).
Chondrosarcoma
Most common in patients between 50 and 60 years of age.The tumour has a predilection for the pelvic bones and a slower growth rate.The main symptom is severe pain that is not relieved by rest and is worse at night.
Conventional radiographs show a lytic lesion centred in the long bone metaphysis, with a permeative growth pattern scalloping the cortex and showing intra-tumoural calcifications, with a flocculent or ring-shaped appearance. The cortex is usually thickened with a slightly expanded and fusiform appearance, mainly due to the slow permeative growth of the tumour (chronic periosteal reaction). Scalloping of the inner cortex is a radiographic sign worrisome for malignancy.Biopsy is the confirmatory test.
Malignant fibrous histiocytoma
Most common in older patients.Frequently presents with pathological fracture.
Conventional radiographs show purely osteolytic tumour with minimal periosteal reaction.Biopsy shows a typical spindle cell pleomorphic sarcoma with storiform architecture.
Giant cell tumour of bone
Most common in skeletally mature women.Usually presents with bone pain and sometimes pathological fractures.
Conventional radiographs show tumour with an osteolytic appearance located in the epiphysis of long bones, with the distal femur and proximal tibia being the most commonly affected. Although benign, the tumour is locally aggressive. This translates radiographically into the absence of an osteosclerotic rim at its periphery as well as the presence of a soft tissue mass. No bone/osteoid formation is identified.Biopsy shows typical appearance of evenly distributed giant cells in a mononuclear stroma. The nuclei of the giant cells resemble the nuclei of the mononuclear stromal cells.
Metastases from other malignancies
Generally occur in older age group than osteosarcoma.Usual history of a primary malignancy known to metastasise to bone, such as breast, lung, thyroid, kidney, and prostate.
Conventional radiographs and radionuclide scans usually show osteolytic lesions (rarely osteoblastic) involving multiple bones.CT imaging may reveal other organs affected by metastatic disease.Biopsy usually confirms the diagnosis.
Lymphoma
More common in older men.Rare as a primary bone neoplasm. Type II general symptoms (e.g., fever, night sweats) and weight loss are common.
Conventional radiographs may be normal (tumour cells tend to grow between patient's bony trabeculae with little bone destruction). There may be multiple or single bone involvement.MRI shows focal change in the marrow signal.Bone marrow biopsy is usually the confirmatory test.Flow cytometric studies should be considered in patients suspected of having lymphoma.
Osteomyelitis
Primary (haematogenous) osteomyelitis is associated with fever, local swelling, and fistula formation.A history of recent trauma with open fracture is significant for secondary osteomyelitis.
C-reactive protein and ESR are markedly elevated.Biopsy shows necrotic bone, fibrotic marrow, and chronic inflammation with or without an acute inflammatory component.Reactive bone is usually produced as part of an associated periosteal reaction.
Langerhans' cell histiocytosis
Tends to have wide age distribution. However, 60% of cases arise in patients younger than 10 years of age.Localised and systemic forms of the disease exist. Has a predilection for the bones of the skull, especially the calvarium, but any other bone can be involved.Local pain and swelling are common.
ESR elevated.Radiographically there are multiple lytic lesions with significant periosteal reaction.Biopsy shows a proliferation of neoplastic Langerhans' cells in an inflammatory background.
Osteoblastoma
Benign osteoid-producing tumour with roughly same age and sex distribution as osteosarcoma.Pain of long duration is the most common presenting symptom.For lesions located in the spine, scoliosis and neurological symptoms may occur.
Conventional radiography reveals a radiolucent lesion in a long bone metaphysis or posterior arch of a vertebra, with a central area of radiodensity secondary to osteoid and bone production. No soft tissue mass is associated with the bone lesion.Biopsy shows osteoid and woven bone rimmed by osteoblasts in a fibrovascular stroma.
Aneurysmal bone cyst
Same age range and location as osteosarcoma.Presents with pain and occasional pathological fracture. Secondary aneurysmal bone cysts can be seen in older patients, superimposed on other primary neoplasms.
Conventional radiographs show radiolucent expansile bone lesion.MRI shows fluid levels on T2-weighted images.Biopsy can differentiate from telangiectatic osteosarcoma, which displays obvious histological features of malignancy (marked cellular pleomorphism, high and abnormal mitotic activity).
Fibrous dysplasia
The presentation of polyostotic fibrous dysplasia commonly includes bone deformity and pathological fracture.Wide age range at presentation and no gender preference.
Conventional radiographs show ground glass appearance with no associated soft tissue mass. There are generally no aggressive radiographical features. Pathological fracture may be seen.

Otitis externa

Acute otitis media
Acute otitis media and AOE present with ear pain. Hearing loss may be present in both. Tympanic membrane may be erythematous in AOE, making it more challenging to rule out either an associated acute otitis media or acute otitis media alone. Pneumatic otoscopy shows mobility of the tympanic membrane in AOE and limited or absent mobility in acute otitis media. [1]
Tympanometry will reveal a normal peaked curve in AOE but a flat (type B) curve in acute otitis media. [1]
Furunculosis
Furunculosis is sometimes referred to as localised AOE. [1] It usually represents a localised infected hair follicle in the cartilaginous portion of the ear canal. [9] The presenting symptoms are similar to those of diffuse AOE. It presents with otalgia and tenderness.On physical examination the infection is confined to the cartilaginous portion of the ear canal. [3] The bony (medial) portion of the external auditory canal is usually normal.
No differentiating tests.
Contact dermatitis of the ear canal
This is an allergic reaction to antigens that could be present in hearing aid material, cosmetics, and other topical otic solutions. Patients usually give history of prior use of topical solutions.Among the topical solutions, neomycin is the most commonly implicated agent. [1] Patients with allergies to otic topical solutions usually present with erythema and oedema that extend into the conchal bowl.
No differentiating tests.
Viral infections of the external ear
Severe otalgia, facial paralysis or paresis, taste disturbance on the anterior two-thirds of the tongue, and decreased lacrimation on the affected side. [1] Physical examination may reveal erythema and/or vesicles in the ear canal and auricle. [3]
No differentiating tests.
Chronic otitis externa
Chronic otitis externa is inflammation of the ear canal skin. It usually presents with diffuse low-grade infection of months' or, at times, years' duration. [8] It is the result of recurrent otitis externa, bacterial or fungal infections, underlying skin conditions, or otorrhoea from middle ear infections. [3] Patients usually present with itching and scant otorrhoea but no pain. [8]Physical examination of the ear varies, depending on the severity of the infection, and can range from dry skin to granulation tissue. [8]
No differentiating tests.
Cancer of the external auditory canal
Recalcitrant to usual medical therapy.
Biopsy of the external auditory canal. [1]
Cholesteatoma
Consider particularly in recalcitrant cases not responding to medical therapy. Otoscopy typically shows crust or keratin in the attic (upper part of the middle ear), the pars flaccida, or the pars tensa (usually posterior superior aspect), with or without a perforation of the tympanic membrane.
CT can help with confirming the diagnosis, assessing disease extension, and treatment planning.

Otitis media

Otitis media with effusion
Typically the middle ear effusion is asymptomatic.
On otoscopy these patients have an effusion of any colour, air fluid levels, or bubbles with normal tympanic membrane landmarks.View image
Myringitis
These patients may have no symptoms attributable to the middle ear.
On otoscopy there is erythema and injection of the tympanic membrane in the neutral position without other features of otitis media.View imageView image
Mastoiditis
There is oedema, erythema, and tenderness over the mastoid process.
Diagnosis is clinical based on history and examination. A CT scan may be warranted if symptoms are severe (to exclude abscess formation) or if the diagnosis is uncertain.
Cholesteatoma
Patients may present with painless otorrhoea and hearing loss. Opacification of the tympanic membrane may lead to a misdiagnosis of AOM.
Diagnosis is based on the history and clinical findings. Imaging is rarely necessary.View image

Ovarian cancer

Irritable bowel syndrome (IBS)
Historically, it is difficult to distinguish ovarian cancer from IBS.Physical examination revealing a pelvic mass should cause suspicion for a non-GI process.
As there is no disease biomarker for IBS, diagnosis is made with the Rome criteria, defined as at least 3 months of abdominal pain or discomfort associated with bowel movements; altered stool frequency, form, or passage; passage of mucus; and bloating.
Metastases to the ovary
Over 50% of metastases to the ovary are from the GI tract (Krukenberg tumours). Approximately 4% of women with GI malignancies have metastasis to the ovary. Breast cancer is another malignancy that can metastasise to the ovary. In general, metastasis to the ovaries tends to be solid and is not associated with ascites. [32]
Imaging may not differentiate between primary organ sites.Colonoscopy and/or upper endoscopy may be used to diagnose cancer originating in the GI tract.Additional tumour markers (CEA, CA 19-9, CA 27-29) should be considered as clinically indicated.Histopathology is usually the distinguishing test.
Endometriosis
Endometriosis occurs in pre-menopausal women, as opposed to ovarian cancer, which occurs in older patients.Pelvic pain is a common symptom for both ovarian cancer and endometriosis, and thus is not helpful in distinguishing the 2 conditions.Approximately 50% of clear cell ovarian carcinomas are associated with endometriosis. The exact nature of this relationship is unclear. [1]
The most sensitive and specific test for the diagnosis of endometriosis, as for epithelial ovarian cancer, is histopathology.
Diverticular disease
May be asymptomatic, and the process is noted as an incidental finding on colonoscopy or barium enema.An acute episode of diverticulitis can be associated with fever, leukocytosis, and left lower quadrant pain. [33]
Barium enema or colonoscopy can be used to diagnose diverticular disease.When active inflammation is present, a CT scan can demonstrate inflammation (seen as stranding) in the sigmoid colon.
Meigs' syndrome
Mainly seen in older women, the triad of ascites, hydrothorax, and a benign ovarian tumour comprises Meigs' syndrome.Signs and symptoms include tachypnoea, tachycardia, and decreased breath sounds usually on the right side.
Investigations may reveal a pelvic mass, electrolyte abnormalities, prolonged prothrombin time, and sometimes elevated CA-125.Chest x-ray confirms pleural effusion, with the U/S or CT showing a mass without metastasis.Thoracentesis and paracentesis are negative for malignant cells.

Ovarian cysts

Ovarian cancer
Post-menopausal woman (>65 years); there may be family history of ovarian cancer or breast cancer (BRCA-1- or BRCA-2-positive), symptoms of dyspepsia, bloating, increased abdominal girth, weight loss, and physical findings of fixed adnexal mass and ascites.
Ultrasound findings of a cyst >10 cm diameter, multi-loculated or with thick-walled septae and solid areas, and high blood flow; elevated CA-125 levels of ≥35 U/mL.Histopathology of the ovary will confirm the diagnosis of ovarian cancer. [43]
Ovarian torsion
Right or left lower quadrant pain. Occasionally presents with mass in the right or left lower quadrant.
Ultrasonography shows ovarian cyst and decreased blood flow.
Polycystic ovary syndrome
Unknown aetiology but present in 6% to 10% of women of reproductive age. The clinical history is usually typical, with menstrual irregularity, infertility, hirsutism, oily skin, scalp hair loss, obesity, and acne.
Pelvic ultrasound is diagnostic if there are 12 or more follicles in each ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume (>10 mL) in either or both ovaries; endometrial lining >5 to 7 mm indicates endometrial thickening. There may be raised serum 17-hydroxy-progesterone, total and free testosterone, DHEAS, and prolactin.
Uterine/broad ligament fibroid
Around 50% of women are asymptomatic. [44] Abnormal menses occurs much more frequently among these patients (30%). [44]
Transvaginal ultrasound: sonolucency of a solid mass that projects from the uterus or broad ligament with a true stalk. [45]MRI: can help further delineate the origin or base of the leiomyoma. [44]
Pelvic inflammatory disease
Usually occurs in women between 20 and 40 years of age.Presents with bi-lateral lower quadrant tenderness, usually within 5 days of the last menstrual period.Purulent discharge from cervical os.
Endocervical swab may confirm pelvic inflammatory disease due to Chlamydia trachomatis or Neisseria gonorrhoeae.
Acute salpingitis
Usually occurs in women between 20 and 40 years of age.Presents with lower quadrant tenderness, usually within 5 days of the last menstrual period.There may be a purulent discharge from cervical os.
Ascending infection is often polymicrobial or due to Chlamydia trachomatis or Neisseria gonorrhoeae.
Tubo-ovarian abscess
The incidence of tubo-ovarian abscess formation among adolescents with a known diagnosis of PID ranges from 17% to 20%. [16]
Ultrasound or CT scan may distinguish this from an ovarian cyst.
Hydrosalpinx
No differentiating signs or symptoms. May result from chronic salpingitis.
Transvaginal ultrasound and MRI can further delineate this from an ovarian cyst.
Endometriosis
A history of painful menstrual cramps (dysmenorrhoea), especially if unrelieved by NSAIDs and progressively worsening and continuous.The prevalence of endometriosis in the general population is 5% to 15%, but the incidence of endometrioma formation has not clearly been identified.Single digit examination followed by bimanual and rectovaginal examinations may reveal pelvic mass (ovarian endometrioma), fixed and retroverted uterus, or uterosacral ligament nodularity and tenderness.
Transvaginal ultrasound is diagnostic for ovarian endometrioma, but may not detect early disease.Rectal endoscopic ultrasound may be of value in patients with suspected deep pelvic endometriosis or involvement of the colon/rectum.Histopathology will confirm the diagnosis of endometriosis or endometrioma, with endometrial-like glandular lining cells and changes of chronic haemorrhage (fibrosis and haemosiderin-containing macrophages) in cyst wall stroma.
Ectopic pregnancy
Missed menstrual period, lower quadrant pain, or pelvic pain with some degree of vaginal bleeding or spotting. Cervical motion tenderness may be present on pelvic examination.
hCG hormone level is high in serum and in urine.Ultrasound reveals an empty uterus and may show a mass in the fallopian tubes.
Threatened miscarriage
Missed menstrual period, abdominal pain, or pelvic pain with vaginal bleeding. May present with haemorrhage and shock.
hCG hormone level is high in serum and in urine.Ultrasound may reveal fetus in the uterus or haemorrhage.
Acute appendicitis
The clinical history is usually typical for appendicitis, with central and right-sided lower abdominal pain and associated fever, anorexia, nausea, and vomiting.
Abdominal ultrasound and CT scan show appendix wall thickening, wall enhancement, and inflammatory changes in the surrounding tissues.FBC shows leukocytosis.
Pelvic adhesions with bowel loops
Gastrointestinal disturbances such as ileus or small bowel obstruction are much more likely due to adhesions; 75% of small bowel obstructions involve adhesions to some extent. [46]
Functional cine MRI: witnesses the visceral slide during Valsalva; 90% accuracy for identifying adhesions of bowel loops. [46]
Crohn's disease
Young adult with fever, nausea, vomiting, diarrhoea, right lower quadrant pain, and localised tenderness, with change in bowel habit, colicky pain, passing of blood and mucus per rectum.
CT scan may show intra-abdominal abscess.Contrast study of the small bowel and colon may show stricture or a series of ulcers and fissures (cobblestone appearance) of mucosa.Colonoscopical appearance shows cobblestone pattern of mucosal ulceration.Histopathology of a large bowel biopsy will show transmucosal inflammation, fibrosis, and scanty granulomas.
Ureteric stone
Pain is usually colicky in nature and severe in intensity. May be referred to the labia and associated with haematuria.Fever usually absent.
Urinalysis positive for blood.Leukocytosis usually absent.Abdominal x-rays or tomogram may show calcified stone.Pyelography and CT scan without oral and intravenous contrast confirm the diagnosis.
Primary tubal cancer
No differentiating signs or symptoms.
Transvaginal ultrasound and MRI can further delineate this from an ovarian cyst.Ultrasound findings include sausage-shaped cystic structures with papillary projections.CA-125 may be elevated in later-stage disease. [8]Doppler imaging may provide added benefit.Histopathology will confirm the diagnosis of tubal carcinoma.
Pelvic varicosities
No differentiating signs or symptoms.
Transvaginal ultrasound and MRI can further delineate this from an ovarian cyst.Doppler imaging may provide benefit.

Ovarian torsion

Ectopic pregnancy
Reproductive-age, sexually active female with missed menses, lower abdominal and pelvic pain, and symptoms of acute abdomen such as diarrhoea, nausea, and vomiting.Presentation may be difficult to distinguish from ovarian torsion.
Positive pregnancy test with beta-hCG level >1500 milli-international units/mL and no intrauterine pregnancy on ultrasound raises suspicion of ectopic pregnancy.
Pelvic inflammatory disease
Sexually active female with lower abdominal pain, cervical motion tenderness, and adnexal tenderness.Abnormal vaginal and cervical discharge may be noted, as well as a temperature >38°C (>101°F).
Cervical cultures may show Neisseria gonorrhoeae or Chlamydia trachomatis, the most common causes of PID.Ultrasound may show tubo-ovarian abscess.
Appendicitis
Acute pain, classically beginning peri-umbilically and localising to the right lower quadrant.
Ultrasound may show a peristaltic or non-compressible structure >6 mm.CT scan may show abnormal appendix diameter >6 mm with wall thickening, wall enhancement, and inflammatory changes in the surrounding tissues.
Mittelschmerz due to ruptured graafian follicle
Diffuse pain, not localised.Occurs mid-cycle, with pelvic pain that resolves.No fever, chills, or discharge.
Clinical diagnosis.
Endometriosis
Cyclic pain exacerbated by onset of menses and occurring during the luteal phase.Pelvic or adnexal mass may be noted, as well as lateral displacement of the uterus.May have chronic pelvic pain.
Definitive diagnosis is surgical.Ultrasound may show ovarian endometrioma (homogeneous, low-level echoes) or deep pelvic endometriosis such as uterosacral ligament involvement (hypoechoic linear thickening).
Urinary tract infection
Pain and tenderness in the suprapubic area commonly associated with burning on micturition.Pyelonephritis may present with fever, chills, and pain at the costovertebral angle.
Urinalysis and urine cultures show presence of bacteria.
Torsion of a para-ovarian cyst or isolated fallopian tube
Clinical picture identical to that of ovarian torsion.
Diagnosis may be available only at the time of surgery.
Ovarian cysts
Lower abdominal pain with adnexal fullness on examination.
Imaging or laparoscopy may be needed to distinguish from ovarian torsion. Ultrasound shows ovarian cysts and lacks features suggestive of torsion.
Urolithiasis
Associated with colic pain, usually in the flank initially and migrating anteriorly and inferiorly as the stone migrates down the ureter.
Ultrasound and CT scan may show hydronephrosis or hydroureter.Urinalysis may show haematuria.

Overlap syndromes

Systemic lupus erythematosus (SLE)
No differentiating symptoms or signs.
Negative for anti-U1-ribonucleoprotein (RNP).High antibody titers to the Smith's antigen or to double-stranded DNA in the absence of anti-U1-RNP suggests SLE as the underlying diagnosis, whereas high titers to anti-U1-RNP suggest mixed connective tissue disease (MCTD).
Polymyositis
More pronounced muscle weakness than is typical of MCTD; Raynaud's phenomenon uncommon.
Negative for anti-U1-RNP.High antibody titers to the Mi-2 antigen or signal recognition particle suggest dermatomyositis or polymyositis rather than overlap syndrome.High-titer antibodies to U1-RNP suggest MCTD; antibodies to the tRNA synthetase enzymes suggest antisynthetase syndrome.
Scleroderma
Digital ischaemia and infarcts more common than in MCTD; truncal sclerodermatous skin changes may also be seen, unlike in MCTD.
Negative for anti-U1-RNP.Antibody titers to anticentromere antibody suggests scleroderma spectrum disease rather than MCTD.Anti-Ku and antipolymyositis/scleroderma point to a scleroderma overlap.
Idiopathic Raynaud's phenomenon
Nail fold capillaroscopy normal, digital infarcts and necrosis not seen; abnormalities suggest underlying connective tissue disease instead.
Negative for anti-U1-RNP.
Vasculitis
Palpable purpura or livedo reticularis suggest small and medium vessel vasculitis that are only rarely seen in MCTD.
Negative for anti-U1-RNP.Positive for antineutrophil cytoplasmic antibody.

Paediatric migraine

Cluster headache
Usually severe in nature; unilateral; orbital, supra-orbital, and/or temporal; and lasts from 15 to 180 minutes.Conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis, and eyelid oedema on the side of the headache are all commonly associated symptoms.
The diagnosis is clinical and there is no specific investigation that will distinguish cluster headache from migraine.
Tension headache
Episodic tension-type headaches are usually bilateral, last from 30 minutes to 7 days, have a pressing or tightening quality, and are not aggravated by physical activity.Nausea, vomiting, photophobia, and phonophobia are not typical accompaniments.
The diagnosis is clinical and there is no specific investigation that will distinguish tension headache from migraine.
Post-traumatic headache
Headaches following a well-defined concussive head injury are not unusual, and are likely to remit over a period of a few days or some weeks.There should have been a notable injury that predated the onset of headaches.A small traumatic extradural haematoma may manifest as persisting headache and vomiting post-injury without other clinical signs.The presence of HTN, bradycardia, altered consciousness level, or any focal neurological deficit suggests a more serious injury or alternative diagnosis and is an indication for urgent CNS imaging. [25]
CT brain: in the absence of a focal neurological deficit, HTN, bradycardia, or altered consciousness level, CT is likely to be normal.
Dental abscess
Presence of fever is a clear indicator that migraine is not a tenable diagnosis.Toothache.History of dental caries.
FBC may demonstrate elevated WBC count, and blood cultures may be positive.
Otitis media
Presence of fever is a clear indicator that migraine is not a tenable diagnosis.Earache.
FBC may demonstrate elevated WBC count, and blood cultures may be positive.
Meningitis
Presence of fever is a clear indicator that migraine is not a tenable diagnosis.Meningism is present.
CSF cultures may be positive in suspected meningitis.
Sinusitis
Presence of fever is a clear indicator that migraine is not a tenable diagnosis.Face pain and nasal discharge.
FBC may demonstrate elevated WBC count, and blood cultures may be positive.
CNS pathology
Less than 1% of children with headache have a brain tumour. Nocturnal or early-morning headaches may be indicative of elevated intracranial pressure secondary to a space-occupying lesion such as a tumour.Altered consciousness level, seizures, inappropriate behaviour (especially if recent onset), increasing head circumference, 'sun-setting eyes', prominent scalp veins, papilloedema, ophthalmoplegia, HTN with or without bradycardia, cranial nerve palsies, motor deficits, and cerebellar signs all suggest a more sinister CNS disorder: for example, tumour, [26] encephalitis, encephalomyelitis, vasculitis/malformation, venous sinus thrombosis, and degenerative disorder.
In children <4 years of age with headaches, neuroimaging should be given strong consideration to exclude a space-occupying lesion.CT/MRI brain and lumbar puncture are normal in migraine and (when indicated) will usually confirm the presence of an alternative pathology.
Refraction error
If old enough, the child may give a history suggestive of myopia or hypermetropia.
Formal assessment of visual acuity confirms the diagnosis of a refraction error as the cause of headaches.
Hypertension
Measurement of BP is mandatory in all children with headaches.
In a child with headaches, the presence of HTN should precipitate a comprehensive search for a cause that is usually renal, vascular, endocrine, or neurological in origin.
Headache of low intracranial pressure
History of a recent lumbar puncture or dural tear.Lying down often relieves low-pressure headaches to some degree.
Diagnosis is clinical.
Toxin-related headache
Substance abuse (e.g., cocaine, marijuana) or poisoning (e.g., carbon monoxide) are elicited in the history.These should be considered when symptoms are atypical and age/social circumstances might suggest that toxin exposure is a theoretical possibility.
Urinalysis will demonstrate the presence of a toxin such as cocaine.Specific site testing is indicated when carbon monoxide poisoning is considered a possibility.
Temporomandibular joint dysfunction
Clinical examination (palpation, movement) should suffice in confirming or excluding the temporomandibular joint as a source of pain.
Diagnosis is clinical.
Obstructive sleep apnoea
This may manifest as early-morning headaches, with accompanying nausea and anorexia, in a child who snores at night with nocturnal arousals and daytime somnolence.
Diagnosis is clinical.
Analgesic headache
Teenagers are at greatest risk.Analgesic use on a daily or near-daily basis should prompt the clinician to consider this diagnosis.
Diagnosis is clinical.

Paget's disease

Osteomalacia
There are no differentiating signs or symptoms.
May have elevated serum 25-hydroxyvitamin D levels, as well as elevated total serum alkaline phosphatase levels. Serum 25-hydroxyvitamin D would be expected to be normal in people with Paget's disease, even if alkaline phosphatase is elevated.
Fibrous dysplasia
There are no differentiating signs or symptoms.
May have elevated serum 25-hydroxyvitamin D levels, as well as elevated total serum alkaline phosphatase levels. Serum 25-hydroxyvitamin D would be expected to be normal in people with Paget's disease, even if alkaline phosphatase is elevated.

Painless lymphocytic thyroiditis

Hashimoto's (chronic lymphocytic) thyroiditis
Patients with permanent hypothyroidism, early or after prolonged follow-up, are indistinguishable from patients with Hashimoto's thyroiditis.
No differentiating tests.
Graves' disease
Exophthalmos, pretibial myxoedema, large goitre, a bruit over the thyroid, and more severe hyperthyroid symptoms.Frequently indistinguishable based on symptoms and physical examination alone. [2]
4-, 6-, or 24-hour radioiodine uptake elevated (or occasionally within the normal range), unless the patient has received a large amount of exogenous iodine (e.g., amiodarone).Increased flow on colour-flow Doppler.
Toxic multinodular goitre
Nodular goitre suggestive of diagnosis but does not exclude painless thyroiditis.
4-, 6-, or 24-hour radioiodine uptake is normal or elevated, but it may be below normal if the patient has iodine-induced hyperthyroidism (e.g., from radiocontrast).Should not be <1% unless the patient has received a large amount of exogenous iodine (e.g., amiodarone).
Factitious ingestion of thyroid hormone
Rare presentation of thyrotoxicosis.Goitre not usually present.May not be distinguishable based on symptoms or examination alone.
4-, 6-, or 24-hour radioiodine uptake and serum thyroglobulin low. [19]
Struma ovarii
Very rare.May present with pelvic discomfort but may not be distinguishable based on symptoms and physical examination alone. [20]
4-, 6-, or 24-hour radioiodine uptake low over the thyroid gland, but measurable over the pelvis.
Subacute (granulomatous) thyroiditis
Fever.Hard and exquisitely tender thyroid gland. [7]
Sedimentation rate (ESR) usually >100 mm/hour.24-hour radioiodine uptake <1%.
Palpation thyroiditis
Clinical diagnosis based on hx of thyroid trauma, for example, parathyroid surgery. [8]
No differentiating tests.
Iodine-induced hyperthyroidism
History of amiodarone use, exposure to radiocontrast.
4-, 6-, or 24-hour radioiodine uptake usually low because of the high iodine content of amiodarone, but may be detectable.Increased flow on colour-flow Doppler.

Pancreatic cancer

Chronic pancreatitis
Because typical symptoms of chronic pancreatitis are also seen in pancreatic cancer, distinguishing between these two diseases can be difficult. Patients may present with pain radiating to the back, malabsorption, malnutrition, and pancreatic endocrine insufficiency. There may be a past history of repeated admission for acute pancreatitis or alcohol abuse.
A few histological features are diagnostic for pancreatic cancer, which can differentiate between pancreatic cancer and chronic pancreatitis. [33]
Bile duct stones
Obstructive jaundice may be painful due to calculous disease. Patients may be younger.
Stones can be demonstrated on abdominal ultrasound, both in the gallbladder and in the bile duct. However, stones may also be seen in patients with pancreatic cancer. ERCP will clarify the situation by ruling out stricture (seen in pancreatic cancer) and confirming bile duct stones, which can be cleared at the time of intervention.
Ampullary carcinoma
Patients may present with iron-deficiency anaemia before presenting with obstructive jaundice. Jaundice may be of a waxing and waning nature due to sloughing of ampullary cancer, resulting in transient resolution of the jaundice.
Upper gastrointestinal (UGI) endoscopy will confirm the presence of ampullary lesion, and biopsy at the time of procedure will verify presence of dysplasia or cancer. A side-viewing endoscope gives a better view of ampullary lesions than the traditional front-viewing endoscope.
Cholangiocarcinoma
Mid- and low bile-duct cancers are indistinguishable on presentation from pancreatic cancer. Both present with painless obstructive jaundice.
Cross-sectional imaging such as CT scan or MRI may reveal absence of pancreatic mass and perhaps thickening of bile duct suggestive of cholangiocarcinomas.
Autoimmune pancreatitis
Almost no distinguishing features between pancreatic cancer and autoimmune pancreatitis.In contrast to pancreatic cancer, autoimmune pancreatitis is at least twice as common in men as it is in women. And, rarely, patients with autoimmune pancreatitis present with symptoms related to extrapancreatic organ involvement (renal, pulmonary, hepatic, gastroduodenal, or involvement of the hypophysis have been reported). [34]
A uniformly enlarged pancreas without duct dilation on axial scanning may prompt serum IgG4 levels or pancreatic biopsy (which may be diagnostic), but this should be managed at a pancreatic centre.

Panic disorders

Specific phobia
Excessive or unrealistic fear of specific objects or situations.Panic sensations are cued by anticipated or actual exposure to the phobic stimuli.
Structured clinical interview.
Social anxiety disorder
Focus of the fear involves concerns over being embarrassed and negatively evaluated by others.Panic sensations are cued by anticipated and actual exposure to social and evaluative situations.
Structured clinical interview.
Post-traumatic stress disorder
Onset follows a potentially life-threatening stressor. Additional differential symptoms include emotional numbing and re-experiencing the trauma.Panic sensations are cued by anticipated and actual exposure to trauma cues.
Structured clinical interview.
Separation anxiety disorder
Symptoms cued by perceived and actual separation from family members.
Structured clinical interview.
Substance-induced anxiety disorder
Symptoms caused by the direct physiological effects of substance use or as a result of its withdrawal.
Structured clinical interview and toxicology screening.

Paracetamol overdose

Shock liver
Shock liver occurs in the setting of sustained hypotension or low-flow state in the liver, which is unusual in paracetamol overdose.
Serum paracetamol level will be negative. However, this is not a definitive differentiating test. By the time liver failure develops, it would be unlikely for the paracetamol level to be detectable.
Acute hepatitis A
There may be a history of travel to an endemic region, foodborne outbreak, close contact with an infected person, or men who have sex with men.
Hepatitis A IgM positive.
Acute hepatitis B
There may be a history of travel to an endemic region, intravenous drug use, contact with an infected person, or men who have sex with men.
Hepatitis B core antigen positive.Hepatitis B surface antigen will be positive 2 to 10 weeks after exposure.
Other hepatotoxins
An important differentiating factor is an exposure history such as exposure to mushrooms (e.g., Amanita phalloides) or herbal preparations (e.g., cascara, chaparral, comfrey, kava, ma-huang).Medications and other exposures include anaesthetic agents (e.g., halothane), industrial chemicals (e.g., carbon tetrachloride, trichloroethylene, paraquat), ACE inhibitors, anabolic steroids, aspirin, calcium-channel blockers, ibuprofen, isoniazid, ketoconazole, methotrexate, naproxen, phenytoin, statins, or valproic acid.
Serum paracetamol level will be negative. However, this is not a definitive differentiating test. By the time liver failure develops, it would be unlikely for the paracetamol level to be detectable.

Paradoxical vocal fold motion

Asthma
Variable severity and periodicity of cough, expiratory wheeze, dyspnoea, hyper-secretions, chest tightness, and tachypnoea.Symptoms show reversibility.
Spirometry: measurement of FEV1 and FVC. Ratio of FEV1/FVC is reduced (expressed as a percentage) indicating airway obstruction.PEFR: reduced, most markedly on waking, and improving through the morning. Compared against predicted value based on gender, age, and height.Bronchodilator challenge: reversibility of airflow obstruction with inhaled beta-2 agonist. Improvement of FEV1 or PEFR of 20% or greater following inhalation of salbutamol is diagnostic.Methacholine provocation test: airway hyper-responsiveness leading to narrowing of the bronchi and subsequent reduced FEV1 in response to inhaled methacholine (bronchoconstrictor).
Laryngomalacia
Congenital disorder, rarely seen in older children, characterised by inspiratory stridor.
Flexible fibre-optic nasendoscopy: decreased laryngeal tone and supra-glottic collapse. [66]
Vocal fold paresis/paralysis
Abnormal voice changes, including increased phonatory effort and altered quality (breathy, hoarse, with possible changes to volume and/or pitch). Damage to both vocal cords (rare) causes difficulty breathing.
Flexible fibre-optic nasendoscopy: weakness or fixation of the arytenoid complex unilaterally or bilaterally.Laryngeal electromyography: decreased or absent nerve input to the thyroarytenoid and/or cricothyroid muscles. [67]
Laryngeal space-occupying lesion (Reinke's oedema, laryngeal carcinoma, laryngeal web, vocal fold polyp)
Voice changes including increased phonatory effort, altered quality and/or loudness, difficulty breathing, shortness of breath, and vocal fatigue secondary to a space-occupying lesion.
Flexible fibre-optic nasendoscopy: visible space-occupying lesion (e.g., Reinke's oedema, laryngeal carcinoma, laryngeal web, or vocal fold polyp). [68]

Paraphimosis

Allergic reactions
History of changes in detergents, or use of new clothing, or cleansing agents in infants, can direct the clinician to the potential for an allergic reaction.
Positive patch test.Avoidance of presumed irritant should ameliorate the symptoms.
Insect bites
History of exposure to insects (typically spiders) should raise the suspicion of insect bites as the cause of penile and foreskin swelling. Additionally, many bites are associated with early onset of necrosis of tissue. Pruritus is often a prominent sign. The site of the bite or sting may be visible.
Antihistamines should reduce redness and swelling.
Tourniquet syndrome
Presence of constricting ring. Use of penile constricting rings to enhance erection by compression of the corpora can also lead to constriction of the glans and foreskin. Sometimes the ring may be so deeply buried in the oedematous tissue as to be almost invisible.
Examination of the penis.
Hair coil strangulation
Presence of hair coil. In infants, hair coil strangulation can lead to significant injury of the corpus and distal oedema of the glans. The hair coil, typically from maternal hair, can be buried in the oedematous tissue and can be difficult to identify.
Examination of the penis.

Parasomnias in adults

seizures (nocturnal)
Nocturnal seizures may be accompanied by incontinence, tongue biting, tonic-clonic movements, and drooling; these symptoms are not noted in the parasomnias.Seizures may also occur when the patient is awake and asleep; parasomnias are always related to sleep. [41]
EEG may show abnormal electrical activity supporting a diagnosis of epilepsy.
narcolepsy
May present with similar features to recurrent isolated sleep paralysis.Narcolepsy patients have other symptoms including cataplexy (sudden focal or generalised loss of tone in the body associated with strong emotional experiences), hallucinations at sleep onset or on awakening, and irresistible sleep attacks.
A multiple sleep latency test (MSLT) following an overnight polysomnogram differentiates narcolepsy from recurrent isolated sleep paralysis.In an MSLT, patients are monitored in the sleep laboratory while having the opportunity to nap.A short sleep latency (<8 minutes) and ≥2 sleep-onset rapid eye movement episodes with these naps indicate a diagnosis of narcolepsy.

Parasomnias in children

Seizures (nocturnal)
Nocturnal frontal lobe seizures may be accompanied by incontinence, tongue-biting, tonic-clonic movements, and drooling. All these features are atypical in the parasomnias.Seizures may occur when the patient is awake or asleep; parasomnias are almost always related to sleep. [4] [25] [44] [50] [51] [52]
Polysomnography (PSG) with expanded electroencephalographic (EEG) measurements: EEG demonstrates abnormal electrical activity consistent with the diagnosis of epilepsy.
Narcolepsy
May present with similar features to recurrent isolated sleep paralysis.Typically has other symptoms, including cataplexy (sudden focal or generalised loss of muscle tone in the body, brought about by strong emotional experiences), hypnagogic or hypnopompic hallucinations at sleep onset or awakening, and irresistible sleep attacks. [53] [54] [55] [56] [57] [58]
Multiple sleep latency tests in narcolepsy demonstrate a mean sleep latency of <8 minutes and ≥2 sleep-onset rapid eye movement (REM) periods (SOREPS). [12]
Periodic limb movement disorder (PLMD)
Parents may report that the child makes rhythmic limb movements during sleep (although not an accurate predictor of periodic limb movement disorder diagnostic index, or PLMS-I).
Polysomnography (PSG) with leg electromyography (assessment enhanced using split-screen, video-polysomnographic analysis): demonstrates typical features. [48] [49]

Parkinson's disease

Progressive supranuclear palsy (PSP)
Gaze palsies and early falls within 1 year of diagnosis. [56]Neurological examination: vertical gaze palsy and significant postural instability.
Evidence of midbrain atrophy on MRI brain can be supportive of PSP diagnosis, but is not definitive.
Multiple system atrophy (MSA; MSA-A, formerly Shy-Drager syndrome; MSA-P, striatonigral degeneration; MSA-C, olivopontocerebellar atrophy)
Poor response to levodopa.Autonomic dysfunction (symptomatic hypotension, urinary urge incontinence, faecal incontinence, urinary retention, persistent erectile dysfunction).Speech or bulbar dysfunction. [57]Pyramidal or cerebellar dysfunction. Neurological examination reveals deficits outside of the extrapyramidal system (i.e., pyramidal, cerebellar or autonomic deficits).
Evidence of pontine and cerebellar atrophy on MRI brain can be supportive of MSA-C diagnosis, but is not definitive.Electromyography (EMG) may demonstrate denervation and reinnervation of rectal sphincter muscle.M-131-iodobenzylguanidine (MIBG) scan may be normal, whereas in idiopathic PD abnormal result expected (available only for research purposes).
Lewy body dementia
Dementia, hallucinations, fluctuating mental status. History is often sufficient for diagnosis.
Neuropsychometric testing may distinguish domains of cognitive deficits.
Corticobasal degeneration
Apraxia, alien limb phenomenon, cortical sensory loss on neurological examination.
None.
Alzheimer disease with parkinsonism
Dementia, aphasia.
Neuropsychometric testing.
Drug-induced parkinsonism
History of neuroleptic, metoclopramide, reserpine, tetrabenazine, lithium, or calcium-channel blocker usage.Symmetrical symptoms. History is sufficient to make diagnosis.
Functional neuroimaging of striatal dopamine transporter uptake, using FP-CIT SPECT, beta-CIT SPECT, or fluorodopa PET, can be helpful in differentiating from neurodegenerative parkinsonism (i.e., scan would be normal in drug-induced parkinsonism).
Metabolic abnormalities
History of hypoxia, hepatocerebral degeneration, hypoglycaemia.Symmetrical symptoms.
Electrolyte testing (laboratory) will demonstrate abnormalities (i.e., liver dysfunction, hypoglycaemia).
Normal pressure hydrocephalus
Dementia, incontinence, prominent gait abnormalities.Rapid or subacute onset.
CT head or MRI brain will demonstrate ventricular enlargement out of proportion to degree of atrophy. MRI flow study may also demonstrate increased CSF flow velocity.Large volume CSF tap may lead to temporary improvement of symptoms.
Structural abnormalities
History of tumour, hydrocephalus, subdural haematoma, or trauma.
MRI brain shows abnormalities consistent with specific aetiology (i.e., tumour=mass; stroke=area of encephalomalacia; subdural haematoma=collection of blood).
Vascular parkinsonism
Lower extremity prominence of symptoms.Symmetrical symptoms.Stepwise progression.Less responsive to levodopa.
MRI brain shows significant small vessel disease or basal ganglia lacunar infarct(s).
Toxin exposure
History of carbon monoxide, manganese, or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure.Acute onset.
MRI brain: abnormalities (T2 changes) in basal ganglia noted.
Infections
History of AIDS, subacute sclerosing panencephalitis, or postencephalitic or prion disease.Acute or subacute onset.
Abnormalities on MRI brain (any changes); serologies (HIV); CSF (any abnormalities).
Hereditary disorders
History of Huntington's disease, spinocerebellar ataxias, Wilson's disease, neurodegeneration with brain iron accumulation (formerly Hallervorden-Spatz disease), parkinsonism-dementia-amyotrophic lateral sclerosis, and mitochondrial cytopathies.Juvenile PD or young onset PD.Associated chorea, myoclonus, cerebellar dysfunction, and dementia.Kayser-Fleischer rings on slit-lamp exam support a diagnosis of Wilson's disease.
Serological genetic testing will identify mutation.Low serum ceruloplasmin and elevated 24-hour urine copper support a diagnosis of Wilson's disease.

Paronychia

Herpetic whitlow
Herpetic whitlow can involve any area of the fingertip or peri-ungual tissues, but only when it causes inflammation of the nail folds does it result in acute paronychia. Therefore, herpes is a known cause of acute paronychia, but herpetic whitlow is a differential in the causes of a painful fingertip.Blistering and increased pain differentiate this from bacterial acute paronychia. [1] [3]
Direct fluorescent antibody: positive staining of HSV.Tzanck smear: multi-nucleated giant cells, inclusion bodies, nuclear moulding.Culture: HSV.PCR: HSV.
Arthropod bite or sting
Itch, hx of bite or travel differentiate this from acute paronychia. [1]
Biopsy is done if lesion is suspicious for malignancy or slow to resolve with treatment.Biopsy will show typical changes of dense inflammatory infiltrate with eosinophils.
Traumatic injury
History of injury differentiates this from acute paronychia. [1]
X-ray for underlying foreign bodies or fracture.
Squamous cell carcinoma or other malignancy such as amelanotic melanoma
Lack of any response to therapy differentiates this from chronic paronychia. [1]
Biopsy shows malignant cells.
Myxoid cyst
Swelling/translucency over nail folds differentiates this from chronic paronychia. [1]
Needling with viscous fluid or trans-illumination, biopsy, MRI.

Paroxysmal atrial tachycardia

Sinus tachycardia
This arrhythmia is usually compensatory for a reduced stroke volume because of heart failure or volume depletion, or because of sympathetic stimulation from pain, fear, or exogenous catecholamines.The presence of a clinical disease state plus variation in the atrial rate will usually differentiate this arrhythmia from atrial tachycardia.
Vagal manoeuvres/adenosine will cause sinus tachycardia to transiently slow down, with slowing of the sinus rate and prolongation of the PR interval before AV block (if it occurs).
AV node re-entry tachycardia
This supraventricular tachycardia shares many of the causes of PAT. Hence, the 2 may be indistinguishable based on history and physical examination.On vagal manoeuvres or administering adenosine, in contrast with PAT, AV node re-entrant tachycardia will abruptly cease. After a pause, sinus rhythm will resume.
The 12-lead ECG may show P waves, which can be differentiated from the P waves of atrial tachycardia by the shortened RP interval created by retrograde activation of the atria.The P waves in atrial tachycardia are found in the second half of the tachycardia cycle (long RP/short PR intervals).
Atrial flutter
This supraventricular tachycardia shares many of the causes of PAT. Hence, the 2 may be indistinguishable based on history and physical examination.Vagal manoeuvres/adenosine will transiently slow the ventricular response rate with AV block. The characteristic flutter waves will be revealed and will be unaffected.
The 12-lead ECG will show a regular tachycardia with the ventricular response rate being a multiple of the atrial flutter rate (usually 300 bpm).Unmedicated flutter will usually present in 2:1 AV block with the ventricular response being 148 to 150 bpm.The flutter waves will typically distort the baseline, particularly in leads II, III, and aVF.When AV block is induced in atrial tachycardia, there is an isoelectric interval between P waves, which is not seen in atrial flutter.

Paroxysmal nocturnal haemoglobinuria

Autoimmune haemolytic anaemia, warm antibody type
Splenomegaly is often present.
The direct antiglobulin (Coombs) test is usually positive.Spherocytes may be present on blood film.Cells lacking GPI-anchored proteins are not present.
Microangiopathic haemolytic anaemia
A reason for microangiopathy (cancer, hypertension, haemangioma, haemolytic uremic syndrome, thrombotic thrombocytopenic purpura) is usually present.
Blood film shows schistocytes.Cells lacking GPI-anchored proteins are not present.
Paroxysmal cold haemoglobinuria
Haemoglobinuria follows exposure to cold. In children, often occurs 2 weeks after a viral infection or immunisation.
Donath-Landsteiner (bithermic haemolysis) test may be positive.Direct Coombs test may be positive with anti-C3d.Cells lacking GPI-anchored proteins are not present.
Myoglobinuria
Evidence of muscle breakdown (pain, hx of trauma, drug hx, etc) present
Urinary pigment is myoglobin.Serum creatine kinase is increased, as is serum alanine aminotransferase and aspartate aminotransferase.Cells lacking GPI-anchored proteins are not present.
Abdominal thrombosis (portal, hepatic veins, mesenteric veins or arteries, renal veins)
From asymptomatic to bouts of abdominal pain, diminished bowel sounds, ascites/varices, bowel perforation, or renal failure. Signs and symptoms depend on the thrombosed vessel.
Cells lacking GPI-anchored proteins are not present.Testing for other sources of thrombosis may be positive

Patellofemoral pain syndrome

Iliotibial band syndrome
Lateral pain.Tenderness on palpation of the iliotibial band 2 to 3 cm superior to the lateral joint line.
Clinical differentiation usually suffices.
Plica syndrome
Medial pain.Tenderness and a palpable band along the medial edge of the patella.
MRI with contrast or arthroscopy for definitive diagnosis.Synovial plicae appear as bands of low signal intensity within the high-signal-intensity joint fluid. [46]
Patellar tendonitis/tendinopathy
Inferior pain.Tenderness of the inferior pole and patellar tendon.
Clinical differentiation usually suffices.
Patellar fat pad inflammation
Inferior pain.Tenderness and swelling deep to the patellar tendon.Pain is aggravated by knee extension.
Clinical differentiation usually suffices.
Patellofemoral osteoarthritis
Deep retropatellar pain.Tenderness and swelling on undersurface of patella.
X-ray findings can show joint-space narrowing, subchondral sclerosis, and osteophyte formation, which are all consistent with osteoarthritis.
Quadriceps tendonitis/tendinopathy
Superior pain.Tenderness of the superior pole and quadriceps tendon.
Clinical differentiation usually suffices.
Chondromalacia patellae/osteochondral defect
Anterior pain.In this condition there is softening of the patellar articular cartilage. It occurs in a subset of patients who present with anterior knee pain.
MRI or arthroscopy is performed for definitive diagnosis.Arthroscopic findings may show softening, blistering, fibrillation, or full-thickness ulceration of cartilage.MRI may show decreased signal areas of patellar cartilage on T1-weighted sequences or osteochondral defect.

Patent ductus arteriosus

Venous hum
A venous hum can be heard usually more on the right side. In addition, it diminishes with supine positioning and with local compression.
Physical examination will distinguish a venous hum as described previously. If there is still sufficient concern echo can be performed. In the case of a venous hum the echo will be normal.
Coronary artery fistula
This murmur is also continuous. However, it is usually heard lower in the precordium. [2]
Can be distinguished by echo. On echo evaluation a coronary fistula will appear as a small continuous jet of flow into the right ventricle or main pulmonary artery. It can be distinguished by location.
Left-sided shunts (ventricular septal defect, atrioventricular septal defect)
These lesions can present similarly with regard to clinical history, ECG, and CXR findings. However, the murmur of most left-to-right shunts will only be heard in systole. The exception is an aortopulmonary window, which is a large connection between aorta and pulmonary artery and will present with clinical findings identical to that of a large PDA.
Echo can definitively distinguish these lesions by their characteristic appearance and location. Left heart enlargement if present will look similar in all these lesions.
Aortic regurgitation
These patients often present at an older age. They can present with symptoms of exercise intolerance as well. The usually do not demonstrate tachypnoea. The murmur is characteristically a high-pitched diastolic decrescendo murmur best heard at the lower left sternal border.
Again echo can definitively distinguish aortic regurgitation from a PDA. On echo, the descending aorta may similarly demonstrate diastolic flow reversal depending on the degree of aortic regurgitation. However, a diastolic regurgitant jet will be seen at the level of the aortic valve.

Patent foramen ovale

Arteriovenous malformation (AVM) in the lung
Patients often have advanced liver disease (e.g., cirrhosis) and may have clubbing, cyanosis or hypoxaemia and/or portal HTN, with splenomegaly, ascites and telangiectasia on the skin of the upper torso.
Doppler imaging shows no colour flow in the interatrial septum.On injection of agitated saline, microbubbles are seen in the left atrium after several cardiac cycles (typically 4 to 8) and not immediately as seen in PFO.A trans-oesophageal echo may further delineate the exact crossover site.If the microbubbles appear in the left atrium without crossing at the fossa ovalis, then AVM is possible.Laboratory findings may show abnormal LFTs, coagulopathy and low serum albumin.Contrast-enhanced CT scanning may illustrate the AVMs.

Pediculosis

Seborrhoeic dermatitis
Dandruff easily falls from the head with scratching, and often can be seen on the shoulder area of clothing.
Diagnosis can easily be confirmed using a hand lens or by microscopic examination. [29]
Other objects in hair
Hair casts, hairspray droplets, scabs, dirt, paint flecks, and even other insects, such as aphids that may get blown into the hair, may be mistaken for head lice or nits.Intense pruritus is usually absent.
Diagnosis can easily be confirmed using a hand lens or by microscopic examination. [29]

Pelvic inflammatory disease

Ectopic pregnancy
Lower abdominal pain, adnexal tenderness, fever and other symptoms of acute abdomen (nausea, vomiting, diarrhoea) may be present. May resemble severe case of PID. PID can exist concurrently with ectopic pregnancy.
Positive pregnancy test will guide search for ectopic pregnancy: hCG hormone level is high in serum and urine.Ultrasound reveals an empty uterus and may show a mass in the fallopian tubes.
Acute appendicitis
Nausea and vomiting occurs in most patients with acute appendicitis. Cervical motion tenderness will occur in about 25% of women with appendicitis while this sign is usually present in all patients with PID.
Abdominal ultrasound: aperistaltic or non-compressible structure with outer diameter >6mm; sensitivity for diagnosis of acute appendicitis is 75%-90%. [19]Abdominal and pelvic CT scan: abnormal appendix (diameter >6 mm) identified or calcified appendicolith seen in association with periappendiceal inflammation; sensitivity for diagnosis of acute appendicitis is 87%-98%. [19]Laparoscopy confirms diagnosis.
Ovarian cyst complications (ruptured ovarian cyst, ovarian cyst torsion, haemorrhagic ovarian cyst)
Ruptured ovarian cyst: rupture usually spontaneous, can follow history of trauma or sexual intercourse; mild chronic lower abdominal discomfort may suddenly intensify. On examination peritoneal signs (guarding, rebound tenderness, rigid abdomen) may be present in lower abdomen and pelvis; adnexal size unremarkable due to collapsed cyst.Ovarian cyst torsion: may present with sudden, acute, unilateral, lower quadrant abdominal pain, severe and colicky in nature; two thirds of patients have nausea and vomiting. Low-grade fever, usually correlates with necrosis; tender adnexal mass palpated in 90%; localised peritoneal irritation.Haemorrhagic ovarian cyst: presents with localised abdominal pain, nausea and vomiting. On examination florid septic or hypovolaemic shock may be present; abdominal tenderness can signify overt peritonitis; pelvic mass may be palpated.
Pelvic ultrasound confirms diagnosis.
Endometriosis
Adnexal enlargement, cervical stenosis or lateral displacement of uterus; cyclic pain that is exacerbated by onset of menses and during the luteal phase; or dyspareunia. Cyclic pain is not a feature of PID.
Transvaginal ultrasound may show ovarian endometrioma or evidence of deep pelvic endometriosis such as uterosacral ligament involvement.Laparoscopy confirms diagnosis by direct visualisation of peritoneal implants with biopsy-confirmed endometrial glands or stroma outside of uterine cavity.
Non-PID causes of vaginal discharge
Vulvovaginal symptoms: discharge, itching, burning, dyspareunia. Vulvovaginal symptoms may or may not present in PID because upper tract disease may exist in the absence of symptoms of vaginitis.
Vaginal discharge tested by wet mount or genetic probe or urethral swab identifies causative organism.
Myofascial pain syndrome
Tenderness confined to 1 anatomic region. Region may be lower abdomen and pelvis. Does not have associated PID features of fever, elevated WBC count, elevated ESR, vaginal discharge and/or positive Neisseria gonorrhoeae and Chlamydia cultures, and adnexal, or cervical tenderness.
Palpation of trigger points produces reproducible pain.

Pemphigus

Familial benign pemphigus (Hailey-Hailey disease)
Does not involve the oral mucosa. Characterised by a dermatitis with superficial erosions primarily in flexural areas of the groin, axilla, and neck.FHx usually exists because of the autosomal dominant mode of inheritance, but onset after the age of 30 years is not uncommon.
The skin biopsy demonstrates no immunoreactants with direct immunofluorescence (DIF) staining. Routine histology is similar to that for pemphigus.
Bullous pemphigoid (BP)
Primarily an autoimmune disease of older people, characterised by tense blisters of the skin, and rarely involves the oral mucosa.Often pruritic and the primary lesion is an urticarial plaque that forms vesicles.Aggressive BP can mimic pemphigus vulgaris (PV). Clinically, the tense blisters of BP differ from those of pemphigus.
BP is distinguished by DIF staining of perilesional skin. A discrete linear band of immunofluorescent staining to IgG, C3, or both is seen along the dermal-epidermal junction.
Linear IgA bullous dermatosis
This condition clinically mimics BP.
Distinguished from pemphigus and BP by its unique DIF staining profile. A discrete linear band of immunofluorescent staining to IgA, C3, or both is seen along the dermal-epidermal junction.
Epidermolysis bullosa acquisita (EBA)
Autoimmune skin disease characterised by tense blisters and fragile skin. Distinguished by the presence of significant scarring. The autoantibody of EBA is directed against type VII collagen, so considerable scarring can occur with this disease.Skin fragility is also prominent, particularly of areas that are exposed to minor trauma, such as the hands, elbows, and knees.
EBA is distinguished by DIF staining of perilesional skin. A discrete broad linear band of immunofluorescent staining to IgG, C3, or both is seen along the dermal-epidermal junction.EBA can be differentiated from BP through the use of salt-split skin staining, in which immunoreactants to IgG, C3, or both are found on the base of the artifactual blister.
Erythema multiforme (EM)
Autoinflammatory skin disease associated with HSV infection, certain medications, and other infections. The classic lesion is a targetoid plaque that is often painful.Constitutional symptoms of fever, lethargy, and myalgia are not uncommon.EM can cause blisters, but when it does, it often causes more tense blisters that are easily distinguishable from pemphigus lesions.
Patients with paraneoplastic pemphigus (PNP) can have lesions that clinically and histologically resemble EM. Often DIF staining is needed in these cases. In EM, DIF staining shows an interface dermatitis with immunofluorescent staining of apoptotic keratinocytes. In PNP, DIF staining can resemble PV or BP, or both, but also has deposition of fibrin in the lamina propria (also seen in lichen planus).
Aphthous stomatitis (ulcers)
Aphthous ulcers are well-demarcated ulcers that occur in the mouth and genital region. They are often painful. They have a self-limited course, lasting 3 to 7 days, can recur, and are associated with stress and fatigue. In contrast, PV is a chronic condition that tends to progress without treatment. The erosions of PV are often not painful early in their course.
The histology of aphthous ulcers is characterised by an infiltrate of lymphocytes, macrophages, and neutrophils in the base of the ulcer. The small vessels and the surrounding epithelium are often involved.
Behcet's disease
The cutaneous manifestation of Behcet's disease that resembles PV is the presence of aphthous ulcers. However, Behcet's is characterised by involvement of other organs that include the eye, central nervous system, GI tract, and GU system.The aphthous ulcers of Behcet's are distinct from the lesions of pemphigus because they appear as punched-out ulcers rather than shallow erosions and blisters. Behcet's may show pathergy (i.e., lesions may develop at sites of minor trauma, e.g., sterile needle prick).
The primary lesion of Behcet's, an aphthous ulcer, is distinguished from pemphigus because it has a distinct pathology. In addition, the pathology of Behcet's can involve the skin vasculature as well as the fat.
Herpetic stomatitis
HSV-1 and HSV-2 cause blisters of the mouth, lips, and skin. HSV-2 is commonly associated with sexual transmission and involves the genital area. HSV-1 more commonly involves the mouth, but also the skin, particularly at sites of minor skin trauma or in patients with eczema (atopic dermatitis).Herpetic stomatitis is due to infection with HSV. The vesicles are often fragile and have a scalloped border.
The presence of HSV on culture or by either a Tzanck smear or a direct fluorescence antibody test differentiates this disease from pemphigus.
Oral lichen planus (LP)
Lichen planus is an autoimmune cutaneous disease that involves the skin, mucosa, and hair follicles.When lichen planus involves the mouth, it is often erosive. It is more common on the buccal mucosa but can also involve the gingiva and lips.Oral lichen planus can resemble the erosions of pemphigus, but typically it also has a lichenoid appearance with a net-like reticulated pattern.
Routine histology and DIF staining of skin or mucosa differentiate lichen planus from pemphigus. In lichen planus, a band of lymphocytes is seen along the dermal-epidermal junction with accompanying apoptosis of basal keratinocytes and saw-toothing of the dermal papillae.DIF findings show staining of apoptotic keratinocytes and a distinct pattern of fibrin staining along the dermal-epidermal junction that extends into the lamina propria.
Stevens-Johnson syndrome (SJS)
A variant of erythema multiforme that involves a large percentage of the cutaneous body surface area and the mucosa. It is a medical emergency often requiring admission to a burn centre.It is frequently associated with the ingestion of a drug or a recent infection.It progresses rapidly, and patients report painful skin. Constitutional symptoms of fever and lymphadenopathy are often present.
Routine haematoxylin and eosin staining of fixed or frozen skin can diagnose the condition.Necrosis of the basal keratinocytes with extension into the superficial dermis and epidermis is seen. DIF findings are non-specific, often demonstrating numerous apoptotic keratinocytes but no distinctive immunofluorescent pattern as seen in pemphigus, BP, or LP.
Toxic epidermal necrolysis (TEN)
A variant of erythema multiforme that involves a large percentage of the cutaneous body surface area and the mucosa. It is a medical emergency often requiring admission to a burn centre.It is frequently associated with the ingestion of a drug or a recent infection.It progresses rapidly, and patients report painful skin. Constitutional symptoms of fever and lymphadenopathy are often present.
Routine haematoxylin and eosin staining of fixed or frozen skin can diagnose the condition.Necrosis of the basal keratinocytes with extension into the superficial dermis and epidermis is seen. DIF findings are non-specific, often demonstrating numerous apoptotic keratinocytes but no distinctive immunofluorescent pattern as seen in pemphigus, BP, or LP.

Peptic ulcer disease

Oesophageal cancer
Presence of alarm features (e.g., weight loss, bleeding, anaemia, vomiting, early satiety, or dysphagia, or if the patient develops dyspeptic symptoms after the age of 55), or family history of upper gastrointestinal cancer, jaundice, a palpable mass, or lymphadenopathy may be indicative of a gastro-oesophageal neoplasm.
Distinguished from peptic ulcer disease by endoscopy: shows mass or irregular ulcer.Diagnosis should be confirmed by endoscopic biopsy.May require additional imaging to diagnose and stage (e.g., ultrasound, CT, MRI).
Stomach cancer
Presence of alarm features (e.g., weight loss, bleeding, anaemia, vomiting, early satiety, or dysphagia, or if the patient develops dyspeptic symptoms after the age of 55), or family history of upper gastrointestinal cancer, jaundice, a palpable mass, or lymphadenopathy may be indicative of a gastro-oesophageal neoplasm.
Distinguished from peptic ulcer disease by endoscopy: shows mass or irregular ulcer.Diagnosis should be confirmed by endoscopic biopsy.May require additional imaging to diagnose and stage (e.g., ultrasound, CT, MRI).
Gastro-oesophageal reflux disease (GORD)
History of heartburn or pain rising from the lower chest to the throat is typical.May have associated laryngitis, cough, and atypical chest pain.
Endoscopy shows absence of gastric/duodenal ulcers and, often, erosions in oesophagus.May require additional testing with ambulatory pH-metry to prove diagnosis.
Gastroparesis
Early satiety prominent.Usually a history of longstanding diabetes with evidence of peripheral neuropathy and other end-organ damage.
Endoscopy may show food stasis.Definitive diagnosis by gastric emptying study (nuclear medicine imaging).
Biliary colic
Pain typically in RUQ, about 30 minutes after meals, waxing and waning over minutes or hours.
Ultrasound or CT scan shows stones in gallbladder and/or bile ducts.
Acute pancreatitis
History of gallstones or alcohol use.Pain typically radiates to back.
Elevated serum amylase and lipase levels.CT scan shows inflammation of pancreas.
Non-ulcer dyspepsia (functional dyspepsia)
Dyspepsia is defined as a discomfort centred in the upper abdomen, commonly related to meals.
A diagnosis of exclusion after finding no relevant abnormality at endoscopy.
Coeliac disease
Diarrhoea and evidence of malabsorption are typical.
Laboratory testing may show microcytic anaemia, iron deficiency, and low calcium and albumin.Anti-tissue transglutaminase antibody has sensitivity and specificity of about 95% for the diagnosis. Anti-endomysial and anti-gliadin antibody tests are less accurate.Endoscopy with duodenal biopsy is the gold standard diagnostic test. Biopsy shows flattening of the villi.
Irritable bowel syndrome
Pain may be indistinguishable from that of peptic ulcer disease, but alteration of bowel habit separates this syndrome.Bloating is also a common complaint.
No specific differentiating tests.
Pleuritic pain
Chest pain altered by respiration.Rub during auscultation through the respiratory cycle.
Chest x-ray may reveal pneumonia or effusion.
Pericarditis
Constant pleuritic central chest pain that is worse in the recumbent position and radiates to one or both trapezius ridges.History of transmural MI, cardiac surgery, neoplasm, viral and bacterial infection, uraemia, dialysis treatment, or systemic autoimmune disorders may be present.A prodrome of myalgias and malaise may be present with any cause of acute pericarditis, particularly in young adults. High or spiking fever may also be present.Pericardial friction rub heard on exam. The rub, when present, is described as high-pitched or squeaky. It is heard best at the left sternal edge with the patient leaning forwards at end-expiration.
ECG shows upwards concave ST-segment elevation globally with PR depressions.Serum troponin is mildly elevated.Chest x-ray may be normal or show a water bottle-shaped enlarged cardiac silhouette.C-reactive protein, ESR, and white blood cells are usually elevated.

Peri-orbital and orbital cellulitis

Insect bites
Local redness of eyelid skin.No fever.Location of insect bite may be visible.
Lyme titres, if Lyme disease is suspected, may be indicated.No other diagnostic tests are available.
Blepharitis
Eyelid margin reveals crusty debris and redness.
Slit-lamp examination reveals redness along the eyelid margin.
Ocular compartment syndrome
Severe eye pain with double vision, vision loss, and/or decreased eye movements, as well as afferent pupillary defects and increased eye pressures.Other symptoms include proptosis, significant conjunctival chemosis, and visual field defects.
Differentiation is only by clinical observation of the factors mentioned. There is no objective differentiating test.
Empyema
Significant headache often present.Other signs of increased cranial pressure can occur, including papilloedema and vomiting.Facial and peri-orbital swelling can mimic peri-orbital and/or orbital cellulitis.Orbital cellulitis can lead to epidural empyemas.
Gadolinium-enhanced MRI is the diagnostic study of choice for empyema and will show fluid collection in the orbit.
Sub-periosteal abscess
Significant pain is usually present as a result of an acute increase in pressure in the sub-periosteal space.
CT scan with contrast shows collection of fluid behind the periosteum.
Orbital pseudo-tumour
Patient may present with pressure symptoms, but it is usually painless.No fever present.
CT scan will show a soft tissue enlargement.
Orbital tumour
Can mimic orbital cellulitis in a variety of ways, depending on size and location.No fever present.
CT scan shows soft tissue growth.Radiologist will provide differentiation from pseudo-tumour in ambivalent cases.

Pericarditis

Myocardial infarction or ischaemia
Chest pain is described as pressure-like, heavy, squeezing, and responsive to glyceryl trinitrate. There is generally no variation with respiration or positional changes. Duration of pain is minutes to hours, rather than hours to days.Pericardial friction rub is generally absent (unless there is associated pericarditis). [5] [10] [1]
ECG may show convex ST elevations in the distribution of coronary arteries; Q waves may be present; PR segment depression is rare; inverted T waves when ST segments are still elevated. Significant elevation of serum troponin and cardiac enzymes present if myocardial damage.
Pulmonary embolism
Chest pain can be anterior, posterior, or lateral in location. It is in phase with respiration (no chest pain when the patient ceases breathing) and is not positional in nature.Pericardial friction rub is rarely present.A pleural friction rub can be detected in 3% of patients. [5] [7] [10] [1]
ECG may show ST-segment elevations limited to leads III, aVF, and V1; no PR depressions; Q waves in leads III and/or aVF; inverted T waves in leads II; aVF, anterior precordial leads while ST segments are elevated.
Pneumonia
Associated with cough and fever. Note that the presence of pneumonia may also be related to the presence of concomitant pericarditis.
Chest x-ray may show evidence of infiltrates.The absence of concomitant ECG findings supporting pericarditis excludes significant pericardial involvement.
Pneumothorax
Many of the signs and symptoms may overlap including sudden onset shortness of breath, tachycardia, and chest pain. Pericarditis pain may be more positional in nature.Physical examination reveals absence of breath sounds, generally unilaterally.Tracheal deviation may also be present.
Chest x-ray confirms lung collapse.
Costochondritis
There is reproducible tenderness with palpation of the costochondral junctions. The pain is exacerbated by moving the trunk.Physical examination is otherwise normal.
Normal ECG.Echocardiography shows no evidence of pericardial involvement.

Periodic limb movement disorder

Nocturnal epilepsy
May be associated with head-turning and involuntary upper limb movements. Postictal confusion may be mistaken for daytime somnolence.
EEG may show evidence of seizure activity. MRI of the brain may demonstrate the structural lesion responsible for seizure activity.
Sleep-disordered breathing
Nocturnal arousals may occur secondary to sleep-disordered breathing. Periodic limb movements of sleep (PLMS) may occur secondary to these arousals. A history of snoring, dry mouth on wakening, and morning headache may be present.
Polysomnography will demonstrate nocturnal hypopnoea, apnoeas, or respiratory effort-related arousals. [1]
Sleep starts
These may be associated with brief contractures of the extremities during sleep.
EMG recordings during polysomnography will differentiate between sleep starts and PLMD.
Rapid eye movement sleep behaviour disorder (RBD)
Body movements may occur as dreams and are re-enacted during rapid eye movement (REM) sleep.
PLMS predominantly occur during stages 1 to 2 of sleep, as demonstrated by EEG during overnight polysomnography. EMG will also differentiate between PLMS and other movements in RBD.
Restless legs syndrome (RLS)
The main symptom of the disorder is the urge to move the legs, which is accompanied by symptoms of dysaesthesias such as creeping, crawling, tingling, cramping, or aching of the extremities. Due to the circadian timing of RLS symptoms, the dysaesthesias can cause insomnia, which can lead to increased sleepiness and tiredness, which in turn increases RLS symptoms.
An initial diagnostic work-up for RLS should include a serum ferritin level.
Iron deficiency anaemia
Patients usually present with fatigue, low energy level, pallor, or dyspnoea on exertion. History specific to iron deficiency as a cause of anaemia includes unusual cravings for ice or non-food items and RLS.
FBC (including haemoglobin and haematocrit, platelet count, MCV, MCH, MCHC, red cell distribution width) with peripheral smear, reticulocyte count, and an iron profile.
Obstructive sleep apnoea
Typical presenting symptoms include excessive daytime sleepiness, restless sleep and episodic gasping, and episodes of apnoea during sleep.
Polysomnography is the definitive test for diagnosis.

Peripheral vascular disease

Spinal stenosis
Patients with history of back pain complain of hip, thigh, buttock, or leg pain. It is usually in a dermatomal distribution and may be associated with motor weakness. The pain may occur on standing alone and is relieved by position change such as sitting or stooping forwards (lumbar spine flexion).
Ankle brachial index (ABI) will be normal and exercise ABI will show no decrease in post-exercise ABI.No significant disease seen with arterial imaging tests.
Arthritis
Patients complain of hip, thigh, or buttock pain that is localised to hip and gluteal region. It can occur at rest or starts after exercise and is not quickly relieved.
ABI will be normal and exercise ABI will show no decrease in post-exercise ABI.No significant disease seen with arterial imaging tests.
Venous claudication
Patients usually have history of iliofemoral DVT, signs of venous congestion, and oedema. They may complain of entire leg pain that is usually worse in the thigh and groin region. The pain is described as tight or bursting and starts after walking and is relieved slowly. Pain relief usually occurs once the leg is elevated.
ABI will be normal and exercise ABI will show no decrease in post-exercise ABI.No significant disease seen with arterial imaging tests.
Chronic compartment syndrome
Occurs in athletes. They complain of tight bursting calf pain after exercise that subsides slowly after leg elevation. Usually these patients are very muscular.
Duplex ultrasound scanning will show no significant arterial stenosis.
Symptomatic Baker's cyst
Patients complain of pain in the calf and behind the knee. The area is usually swollen, sore, and tender. The pain is present at rest and worse with exercise.
ABI will be normal and exercise ABI will show no decrease in post-exercise ABI.No significant disease seen with arterial imaging tests.

Personality disorders

Mood disorders
Symptoms develop over much shorter periods of time and represent a change in functioning; [1] include somatic symptoms, such as insomnia, weight loss, or psychomotor agitation. [1]Consider personality disorder as a comorbid condition.
Clinical interview.Use of DSM-IV criteria. [1] [45]The Primary Care Evaluation of Mental Disorders (PRIME-MD) [39] may indicate presence of symptoms suggestive of mood disorders.Mood Disorder Questionnaire [43] may indicate presence of symptoms indicative of elevated mood states (hypomania and mania).Patient Health Questionnaire-9 (PHQ-9) [40] [Patient Health Questionnaire- 9 (PHQ-9)] may indicate presence of self-harm, suicidal ideation.
Psychotic disorders
Absence of persistent delusions and hallucinations in personality disorder. [1] However, patients with borderline personality disorder may experience transient paranoid ideation in response to stress; patients with schizotypal personality disorder may experience ideas of reference (but not delusions), as well as odd beliefs or magical thinking. [1]Consider personality disorder as a comorbid condition.
Clinical interview.Use of DSM-IV criteria. [1] [45]
Anxiety disorders
Avoidance behaviour in agoraphobia is circumscribed and in relation to occurrence of panic attacks (compared with avoidant personality disorder in which avoidance behaviour is evident in a variety of settings involving interpersonal contact).Presence of obsessions and compulsions in obsessive-compulsive disorder (compared with obsessive-compulsive personality disorder where perfectionistic traits are apparent).Consider personality disorder as a comorbid condition.
Clinical interview.Use of DSM-IV criteria. [1] [45]Generalised Anxiety Disorder-7 (GAD-7) or GAD-2 [41] [42] may indicate presence of symptoms suggestive of anxiety disorders.
Substance-related disorders
For antisocial personality disorder diagnosis to be given in addition to a substance-related diagnosis, antisocial personality disorder symptoms must have been present in childhood (typically prior to the establishment of the substance-related disorder) and continued into adulthood. [1]Consider personality disorder as a comorbid condition.
Urine drug screen.Clinical interview.Use of DSM-IV criteria. [1] [45]The Primary Care Evaluation of Mental Disorders (PRIME-MD) [39] may indicate presence of symptoms suggestive of alcohol abuse/dependence.
Personality change due to general medical condition
Personality symptoms represent a change from baseline level of functioning and are due to a direct physiological cause (e.g., head trauma, endocrine condition, or other conditions with CNS). [1]
Clinical interview with patient and, if possible, collateral source.Use of DSM-IV criteria. [1] [45]Imaging (CT/MRI of brain) or laboratory tests (urine drug screening) may have suggestive findings.
Sub-threshold personality traits
Traits that are not considered rigid, maladaptive, stable, and linked to impairment.
Clinical interviewUse of DSM-IV criteria [1] [45] to rule out personality disorder diagnosis

Pertussis

Upper respiratory infection
Lack of whooping-type cough. [2] [3] [4] [1] [33]
Culture: negative result for B pertussis
Community-acquired pneumonia (CAP)
Lack of whooping-type cough. [2] [3] [4] [1] [33]Fever, history of productive cough, history of respiratory disease (e.g., asthma). Signs of pneumonia on auscultation.
Culture negative result for B pertussis or positive for pathogens associated with community-acquired pneumonia (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae). [2] [3] [4] [1] [20] [33]CXR may show evidence of infiltrates in primary CAP or if patient develops pneumonia as a complication of pertussis. CXR is normal in uncomplicated pertussis.
Respiratory syncytial viral (RSV) infection
Extremes of age (infants and elderly), history of prematurity in infants, coryza, conjunctivitis, sinus/ear involvement, wheezing, dyspnoea, use of accessory muscles of respiration. History of community outbreak. Lack of whooping-type cough. [2] [3] [4] [1] [33]
Culture: negative result for B pertussis.RSV infection diagnosis can be made by virus isolation, detection of viral antigens, detection of viral RNA, demonstration of a rise in serum antibodies, or a combination of these approaches. Most clinical laboratories use antigen detection assays to diagnose infection.

Peutz-Jeghers syndrome

Juvenile polyposis syndrome
Polyposis is more likely to occur in the colorectum. Increased prevalence of massive gastric polyposis and of hereditary haemorrhagic telangiectasia. Mucocutaneous pigmentation is absent.
Germline testing for MADH4 and BMPR1A gene mutations will be positive.
PTEN-hamartoma tumour syndrome
Clinical presentation may be similar. Macrocephaly is a common feature. Patients may have cutaneous lesions including trichilemmomas and papillomatous papules.
Germline testing for PTEN gene mutations will be positive.
Mixed hereditary polyposis syndrome
Clinical presentation may be similar. Mucocutaneous pigmentation is absent.
Germline testing for BMPR1A gene mutations will be positive.
Familial adenomatous polyposis
Clinical presentation may be similar. May have other extra-colonic features (e.g., osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium, desmoid tumours, and adrenal masses). Mucocutaneous pigmentation is absent.
Endoscopy may show adenomatous, rather than hamartomatous, polyps throughout the colorectum. Germline testing for APC gene mutations will be positive.
Hereditary non-polyposis colorectal cancer
Patients may develop a few adenomas over their lifetime but not hamartomatous polyps. Mucocutaneous pigmentation is absent.
Germline testing for MLH1, MSH2, MSH6, or PMS2 gene mutations will be positive.Detection of MLH1, MSH2, MSH6, and PMS2 mutations on colorectal or endometrial cancer tissue.
Carney's complex
Polyps are not known to occur as part of Carney's complex.Patients may have a hx of myxomas (heart, skin, and breast), endocrine dysfunction and tumours, and schwannomas.
Germline testing for PRKAR1A gene mutations will be positive.

Phaeochromocytoma

Anxiety and panic attacks
Careful history-taking is required to differentiate these conditions from a phaeochromocytoma.It is important to assess the patient's mental state, and enquire about phobias and other psychiatric conditions.Panic attacks and anxiety are often situational, whereas symptoms associated with a phaeochromocytoma are episodic in nature.
Diagnosis is clinical.These patients will not have biochemical evidence of hypercatecholaminaemia when they are not having a panic attack.
Essential or intractable HTN
The presence of symptoms such as headache, palpitations, and diaphoresis are all suggestive for a phaeochromocytoma, especially in the setting of HTN.
Phaeochromocytomas can usually be ruled out with measurement of urine metanephrines, normetanephrines, and catecholamines.Paroxysmal, drug-resistant HTN is more suggestive for a phaeochromocytoma. In contrast, essential HTN is drug-responsive and easier to treat.
Hyperthyroidism
May mimic a phaeochromocytoma as it is also associated with diaphoresis, palpitations, tremors, and weight loss.
Depressed TSH levels support a diagnosis of hyperthyroidism in the setting of an elevated free thyroxine level.Urinary work-up studies for a phaeochromocytoma would be negative.
Consumption of illicit substances
Certain recreational drugs such as cocaine and amphetamines can cause symptoms similar to those of a phaeochromocytoma.
Toxicology may be useful if drug abuse is suspected as catecholamine and metabolite levels may be acutely raised after consumption of these substances, making it difficult to distinguish from a phaeochromocytoma.
Carcinoid syndrome
This syndrome is characterised by periods of intense flushing usually associated with diarrhoea, cramping, pulmonary wheezing, and tricuspid valve and pulmonary valve abnormalities.Carcinoid tumours are characteristically associated with a skin flush; in contrast, phaeochromocytomas are associated with pallor.
Carcinoid is diagnosed by increased urinary secretion of 5-hydroxyindole acetic acid, as well as a biopsy of the tumour.
Cardiac arrhythmias
Can also present with symptoms similar to those caused by a phaeochromocytoma: namely, palpitations.Rarely, an underlying phaeochromocytoma may actually be the precipitant of an arrhythmia (e.g., SVT, ventricular fibrillation).
Negative ECG/telemetry/Holter monitoring while the patient is symptomatic can rule out this diagnosis.Catecholamines and metanephrines will be high in a phaeochromocytoma and normal in patients with an isolated arrhythmia.
Menopause
Symptoms of the menopause may mimic a phaeochromocytoma.Patients commonly complain of perfuse sweating and flushing.In contrast, patients with a phaeochromocytoma have profuse sweating associated with pallor.
Catecholamines and their metabolites are not elevated during the menopause.
Pre-eclampsia
Typically, presents beyond 20 weeks of pregnancy; therefore, usually not a likely differential in most patients.Phaeochromocytomas present a rare diagnostic and therapeutic challenge in the pregnant woman. [18]Pre-eclampsia is associated with oedema, which is not a feature of a phaeochromocytoma.
Pre-eclampsia patients have proteinuria and usually an elevated blood uric acid; these values are normal in patients with a phaeochromocytoma.Catecholamines and metanephrines will be high in a phaeochromocytoma and normal in patients with pre-eclampsia.

Phenylketonuria

Inborn errors of tetrahydrobiopterin (BH4) synthesis
Hyper-phenylalaninaemia can also result from rare defects in BH4. If untreated, these patients would develop mental retardation, movement disorders, seizures, and other neurological symptoms despite control of blood phenylalanine (phe) level. [9] Much less common than PKU.
Urine neopterin to biopterin ratio will be increased in defects of biopterin synthesis.Dihydropteridine reductase (DHPR) assay will be low in patients with DHPR deficiency.
Hepatic dysfunction
May have hepatomegaly, jaundice.
LFTs will be abnormal.Usually multiple elevations of plasma amino acids will be noted, not just phe.
Extreme prematurity
Baby will typically be in NICU. Small size and history of premature delivery.
Usually multiple elevations of plasma amino acids will be noted, not just phe.

Phobias

Panic disorder with or without agoraphobia
High anticipatory anxiety across various social situations.Recurrent, unexpected panic attacks in the absence of phobic cues.Patients may interpret their intense physical symptoms as threatening or dangerous.
Structured clinical interview.
Social anxiety disorder (social phobia)
Fears involve concerns over being embarrassed and negatively evaluated by others.The DSM-IV introduced the alternate diagnostic label of Social Anxiety Disorder to help reduce confusion over the use of the term phobia. It is likely that the DSM-V will exclusively use the term Social Anxiety Disorder to assist in the differentiation of this condition from specific phobias.
Structured clinical interview.
Post-traumatic stress disorder
Onset follows potentially life-threatening stressors. Emotional numbing is common.Re-experiencing of traumas is common.
Structured clinical interview.
Separation anxiety disorder
Fears involve perceived separations from family members.
Structured clinical interview.

Pilonidal disease

Perianal fistula
The opening is located in the perianal region, and the skin of the natal cleft is normal.Patients may report rectal discharge of mucus.
There are usually no differentiating tests. Diagnosis is clinical.
Perianal abscess
The abscess develops in the perianal region, and the skin of the natal cleft is normal.
There are usually no differentiating tests. Diagnosis is clinical.
Hidradenitis suppurativa
May occur in the perineal/perianal region, but also in the areolar area of the breasts and frequently in the axillae.
There are usually no differentiating tests. Diagnosis is clinical.
Infected sebaceous cyst
Occurs anywhere in the body. There may be a history of a small preceding skin lesion. Infection of the cyst is characterised by swelling and pain. In about one half of cases a punctum will be visible.
There are usually no differentiating tests. Diagnosis is clinical.
Sacral osteomyelitis
Infection of the underlying sacral bone may also cause pain and tenderness, but the overlying skin should be normal.Much less common than pilonidal disease.
Bone scan, x-rays, CT, or MRI shows evidence of osteomyelitis.Blood cultures may be positive for aetiological organism.

Pinworm infection

Inflammatory bowel disease
Typically, presents with prominent GI signs as well as evidence of systemic disease such as fever and weight loss.
Colonoscopy/ileoscopy will show mucosal inflammation or ulceration. The biopsies will confirm inflammatory changes.
Dermatitis, atopic
People with pinworm infection should not have evidence of inflammation or excoriation outside of the perineal area.
Eosinophilia is uncommon in pinworm infection but may occur in eczema.
Perirectal abscess
Children with perirectal abscess are more likely to present with fever and pain. Abscess formation is extremely rare in pinworm infection.
Acute-phase reactants are elevated in abscesses. Ultrasound/CT will confirm diagnosis.

Pituitary adenoma

Prolactin secreting adenoma (prolactinoma)
The presence of galactorrhoea suggests prolactinoma.While macroprolactinomas may present with similar clinical pictures to nonfunctional pituitary macroadenomas, microprolactinomas in pre-menopausal women may present with amenorrhoea and galactorrhoea, and with impotence and lack of libido in men. Hypogonadism in non-functional pituitary microadenomas is rare.
Need to consider serial dilution in those with large pituitary macroadenomas (>3 cm) to rule out hook effect secondary to very high prolactin levels, which results in only mild to moderate elevation of assay reported prolactin level (not necessary in labs using 2-step assay for prolactin measurement). [38]
GH secreting adenoma (acromegaly)
These are macroadenomas in about 75% of cases. Patients typically have coarsening of facial features and acral enlargement.Other signs and symptoms may include skin tags, macroglossia, HTN, arthropathy, hyperhidrosis, symptoms associated with sleep apnoea and glucose intolerance/diabetes.
An age- and sex-matched IGF-1 is typically elevated and patients fail to suppress GH to less than 1 microgram/L (1 nanogram/mL) during oral glucose tolerance test.The immunostaining of the tumour will show diffuse staining for GH and may also be positive for prolactin.
ACTH-secreting adenoma (Cushing's syndrome)
These tumours are typically microadenomas and cause classic symptoms of Cushing's syndrome, including skin atrophy, easy bruising, facial plethora, central adiposity, muscle wasting and wide (>1 cm) purplish striae.
Hypercortisolaemia is documented with an elevated 24-hour urinary free cortisol, elevated midnight salivary cortisol or lack of cortisol suppression (<50 nanomol/L [<1.8 microgram/dL]) during 2 days low-dose dexamethasone suppression test.The immunostaining of the tumour will show diffuse staining for ACTH and patients would develop adrenal insufficiency after successful resection of an ACTH-producing pituitary adenoma.
TSH secreting adenoma
Patients present with typical features of hyperthyroidism such as palpitation, tremor, weight loss and diaphoresis.The pituitary tumour is usually a macroadenoma.
The free T4 and free T3 levels will be elevated in the setting of a normal or slightly elevated TSH. The alpha subunit is usually elevated.The immunostaining of the tumour will show diffuse staining for TSH.
Rathke cleft cyst
Rathke pouch remnants may develop to cysts of different sizes and be localised in the sellar and suprasellar region.Rathke cleft cysts are usually discovered incidentally but rarely may present as space-occupying lesions and be associated with mass effect such as hypopituitarism.
The CT feature of Rathke cleft cyst consists of a low-density, well-circumscribed, non-enhancing sellar mass that may be associated with suprasellar extension. On MR images, Rathke cleft cysts may show various signal intensities but frequently are hyperintense on T2-weighted image.
Craniopharyngioma
Commonly seen in children but also has a second peak in adults in their sixth decade.Patients may present with symptoms related to diabetes insipidus, such as polyuria, polydipsia and nocturia.
A cystic suprasellar lesion would suggest craniopharyngioma. Presence of calcification, which is best seen on CT scan, in up to 70% of patients would further support the diagnosis.
Meningioma
Meningiomas occur more frequently in women with a peak age between 40 and 50 years.
A dense homogenous enhancement on MRI and the presence of calcification on CT scan supports the diagnosis. The presence of a dural tail sign would suggest the diagnosis.
Hypophysitis
Nine times more common in females and commonly affecting young women during late pregnancy or in the postpartum period.There is increased association with other auto-immune disorders such as Hashimoto's thyroiditis.
The chronologic association with pregnancy or postpartum and isolated ACTH deficiency may be clues to its diagnosis.
Sarcoidosis
Neurosarcoidosis is seen in about 5% to 10% of individuals with sarcoidosis. It is more common in African Americans and frequently occurs in adults aged 25 to 50 years.It can be associated with various degrees of hypopituitarism and diabetes insipidus.
Among suggestive MRI findings include thickened pituitary stalk and leptomeningeal enhancement. Patients should have chest radiograph to look for systemic disease. The definitive diagnosis requires biopsy.
Infections
Most patients with pituitary abscess present with symptoms related to mass effect (including headache), which at times can be very debilitating.Pituitary tuberculoma presenting as an isolated CNS lesion, without systemic involvement, is very rare.
The differentiation of pituitary abscess from non-functioning adenomas is difficult both clinically and radiologically. Pituitary abscess may be seen as a non-enhancing sellar mass with thick wall on MRI imaging.
Pituitary hyperplasia
Enlarged pituitary gland secondary to pituitary hyperplasia can be seen in pregnant women, patients with primary hypothyroidism, primary hypogonadism and post-menopausal women.Proper identification is important to prevent unnecessary surgery.
The MRI usually shows an enlarged hill-shaped sellar mass thath enhances homogenously following contrast.
Vascular aneurysm
Suprasellar or intrasellar aneurysms of the carotid arteries or suprasellar aneurysms of the anterior and posterior communicating arteries can clinically resemble expanding pituitary tumours.Based on their location, they may present with mass effect (e.g., visual field deficit and hypopituitarism).
Aneurysms of sellar region may present with various signal intensities on MRI if partially thrombosed. MR angiography is used to confirm the diagnosis.
Metastatic lesions
There is usually a known history of malignancy, typically from breast, lung and kidney cancers.
CT and MRI findings may suggest the diagnosis with extensive bony erosion, pituitary stalk thickening and heterogeneous sellar mass. Diabetes insipidus is a common clinical finding in up to 70% of patients. [39] Rapid tumour growth on follow-up MRI supports the diagnosis.

Pityriasis lichenoides

Lymphomatoid papulosis
Lymphomatoid papulosis can clinically resemble pityriasis lichenoides, yet the lesions are more nodular as opposed to popular. Unlike pityriasis lichenoides, it presents around the fifth decade and has a higher likelihood to develop into cutaneous lymphoma. [13]
Skin biopsy will show nodular infiltrate of atypical lymphocytes (some CD30+ with epidermotropism). [13]
Guttate psoriasis
Clinical examination of multiple pink, flat papules with prominent scale mostly scattered on the torso differentiates this entity from pityriasis lichenoides. [1]
Skin biopsy will demonstrate regular acanthosis and hypergranulosis. [13]
Drug eruption
Clinical examination of generalised pink-to-red macules and papules, usually absent of scale, crust, or ulceration, and history of recent medication changes.
No differentiating tests recommended; drug eruption is a clinical diagnosis.
Syphilis infection (secondary)
History of sexual activity and possible primary chancre. Polymorphic, multiple, pink-to-brown macules and papules in a diffuse distribution on clinical examination. Frequent involvement of palms and soles and accompanying mucosal ulcers.
VDRL/RPR laboratory test is positive.
Lichen planus
The lesions of lichen planus will be more purple, pruritic and polygonal. [1]
Skin biopsy will show irregular acanthosis and lichenoid dermal infiltrate. [13]

Pityriasis rosea

Secondary syphilis
Palmoplantar involvement common, orientation of lesions more random, possible history of primary genital ulcer, positive risk factors. [2] [3] [8]
RPR/VDRL serology positive.
Guttate psoriasis
Usually follows streptococcal infection, small erythematous papules with micaceous white scale, no particular orientation. [3] [16]
Antistreptolysin O titres positive.Skin biopsy will demonstrate regular acanthosis and hypergranulosis.
Tinea corporis
Usually single or few lesions, may resemble herald patch. No prodromal symptoms, no subsequent eruption. [3] [16]
Fungal culture positivity, hyphae on potassium hydroxide (KOH) preparation.
Drug eruption
Rash between 5 and 20 days after initiating medicine, protracted course, no herald patch, lesions more likely to be bright red or violet, pruritus severe. [7]Medication hx including recent use of: ACE-inhibitors, aspirin (acetylsalicylic acid), allopurinol, arsenics, barbiturates, beta-blockers, bismuth, clonidine, d-penicillamine, gold, hydrochlorothiazide, isotretinoin, levamisole, meprobamate, methopromazine, metronidazole, nimesulide, non-steroidal anti-inflammatory drugs, omeprazole, sulphasalazine, terbinafine, tyrokinase kinase inhibitors, diphtheria toxoid, BCG/hepatitis B virus/pneumococcal vaccines. [2] [3] [6] [7] [16] [17] [18] [19]
Histopathology more consistent with drug eruption-increased dermal eosinophils. [18]
Nummular eczema
Lesions are discrete, round, more likely to have generalised scale rather than collarette, usually xerotic. [3] [17]
Clinical diagnosis.
Pruritic urticarial papules and plaques of pregnancy
Discrete pruritic papules and plaques over trunk in primigravida pregnant women in the third trimester, usually predilection for striae; sparing of umbilicus; no herald patch. [15]
Clinical diagnosis.
Pityriasis lichenoides chronica
Longstanding eruption of flat-topped papules with fine scale, no particular orientation, duration months or longer; no herald patch. [3]
Clinical diagnosis.
Pityriasis (tinea) versicolor
Minimal fine scale, salmon pink to hypopigmented to hyperpigmented macules confluent into patches over chest and back. No herald patch. More central and superiorly located, no skin cleavage line predilection, minimal to no pruritus.
Spores and hyphae on KOH preparation.

Pityriasis versicolor

Vitiligo
Primarily affects acral areas of the body such as the hands and feet, as well as the face. Depigmented, rather than hypopigmented, lesions with no associated scale.Highlighting of depigmented areas with Wood lamp viewing but no fluorescence in lesions of vitiligo. In addition, vitiligo is usually distributed in a symmetric pattern, whereas the hypopigmented lesions of PV may or may not be symmetric.
Microscopy: negative with KOH preparation.Skin biopsy demonstrating absent melanocytes in affected skin with no hyphae or spores within the stratum corneum.
Tinea corporis
Inflammatory (red) annular plaques with leading-edge scale, central hypopigmentation, and folliculocentric pustules on any body surface.Inflammatory lesions are often associated with pruritus.No fluorescence with Wood lamp viewing.
Septate hyphae with no yeast on KOH preparation.Dermatophyte fungus (usually Trichophyton rubrum) on Sabouraud mycological media.Skin biopsy demonstrates septate hyphae, with no yeast, in the stratum corneum, and frequently reveals an inflammatory infiltrate.
Seborrhoeic dermatitis
Often associated with PV and occurs in similar distribution on the trunk. However, seborrhoeic dermatitis is also often present on the scalp, face, ear canals, groin, and gluteal crease.Erythema and pruritus common.No associated pigmentary abnormalities.No fluorescence on Wood lamp viewing. Seborrhoeic dermatitis can be seen in all age groups.
Microscopy: yeast may be present on KOH preparation. However, associated hyphal forms are absent.Skin biopsy does not demonstrate the characteristic short hyphae and budding yeast of PV, and instead often reveals pronounced epidermal spongiosis, acanthosis, and an inflammatory infiltrate.
Pityriasis rosea
Similar scale to PV but no associated hypopigmentation. Erythematous discrete macules, often pruritic, on the entire trunk with a Christmas tree pattern (individual lesions run parallel to the lines of skin cleavage). Begins with a solitary 'herald patch' before abrupt onset of eruption and resolves over 3 to 8 weeks with no chronicity or recurrence.No fluorescence with Wood lamp viewing.
Microscopy: negative with KOH preparation.Skin biopsy does not demonstrate fungal forms and instead reveals epidermal acanthosis, spongiosis, mounding parakeratosis, and lymphocytic inflammation.
Pityriasis alba
Frequently seen on the faces and arms of children with underlying atopic dermatitis.No fluorescence with Wood lamp viewing.
Microscopy: negative with KOH preparation.Skin biopsy does not demonstrate fungal forms and instead reveals mild epidermal spongiosis, and hyper- and parakeratosis with absent to mild lymphocytic inflammation.
Erythrasma
Sharply demarcated brown scaly patches localised to intertriginous areas of the axillae, genitocrural crease, and web spaces of the toes.Wood lamp examination, the optimal diagnostic tool, demonstrates coral red fluorescence instead of the yellow seen in PV.
Microscopy: negative with KOH preparation.Skin biopsy does not demonstrate fungal forms and instead reveals gram-positive coccobacilli (often appear filamentous on haematoxylin-eosin-, periodic acid-Schiff-, or Giemsa-stained sections) in the stratum corneum.
Confluent and reticulated papillomatosis of Gougerot and Carteaud
Faintly erythematous to hyperpigmented, slightly scaly macules and patches in the intermammary and upper trunk similar to PV. However, no hypopigmentation. Confluent lesions on the central chest with reticulated peripheral borders.No fluorescence with Wood lamp viewing.
Microscopy with KOH preparation often reveals budding yeast with no hyphae (no spaghetti-and-meatballs appearance).Skin biopsy demonstrates mild hyperkeratosis and papillomatosis limited to the valleys between elongated papillae. Yeast often present but no hyphae.
Melasma
Hyperpigmented patches with no overlying scale on the face of young women.No fluorescence with Wood lamp viewing.
Microscopy: negative with KOH preparation.Skin biopsy rarely needed.
Secondary syphilis
Variety of presentations. Often presents with sharply demarcated, erythematous papules with overlying scale on the trunk, face, groin, and extremities with characteristic involvement of palms and soles. Mucus membrane lesions and generalised lymphadenopathy often present.Negative Wood lamp examination.
Microscopy: negative with KOH preparation.Positive non-treponemal and treponemal serological testing.Skin biopsy demonstrates psoriasiform epidermal hyperplasia with a band-like and perivascular plasma cell-rich infiltrate. Spirochetes on silver-stained sections with no fungal forms on periodic acid-Schiff- or Grocott-Gomori methenamine silver-stained sections.
Pinta
Eruption begins with erythematous plaque with satellite papules that eventually become hyperpigmented and heal with depigmented macules primarily on the face, waistline, wrist flexures, and trochanteric region. [2]Seen only in areas of the Brazilian rain forest.Negative Wood lamp examination.
Microscopy: negative with KOH preparation.Darkfield microscopy examination of lesions shows spirochetes.

Placental abruption

Preterm labour
Preterm labour and placental abruption may co-exist. Careful clinical assessment is essential to differentiate between preterm labour and abruption (10% of idiopathic preterm labour is due to placental abruption).Bleeding is light rather than moderate-to-heavy.
Ultrasound may be helpful. Positive findings may be diagnostic of abruption. Preterm labour generally is associated with a normal ultrasound and generally does not result in fetal heart rate abnormalities or DIC.
Placenta praevia
Classically presents with painless vaginal bleeding; however, painful contractions may accompany this.Bleeding when placenta praevia has been excluded by ultrasound should be considered to be due to abruption until shown otherwise.
A sonogram, including a search for ultrasound signs of abruption and sonographic assessment of the area over the cervix, may be useful in distinguishing between the 2 conditions. In placenta praevia, the placenta will be seen overlying the internal cervical os.Occasionally, trans-vaginal sonography may be used to examine the lower uterine segment in order to exclude placenta praevia.
Chorioamnionitis
Bleeding is uncommon.Fever may be present.
Careful clinical assessment is required; however, WBC count may be elevated.
Acute appendicitis
No vaginal bleeding.Pain is typically located to either the RLQ or peri-umbilical region.Frequently associated with a loss of appetite, vomiting, and fever.
Elevated WBC count is typical.CT scan or an ultrasound may show evidence of appendicitis.
Acute pyelonephritis
No vaginal bleeding.Frequently associated with dysuria, fever, rigours, flank pain, and costovertebral angle tenderness.
Elevated WBC count.Urine microscopy typically shows evidence of white cells and bacteria on Gram stain.Urine dipstick testing will be positive for leukocyte esterase and nitrites.Positive urine culture is confirmatory.
Urinary tract infection
No vaginal bleeding.Typically presents with dysuria and supra-pubic pain.
Urine dipstick testing will be positive for leukocyte esterase and nitrites.Urine microscopy will reveal WBC and bacteria.Culture identifies causative organisms.
Degeneration of uterine fibroids
No vaginal bleeding.Fibroids may occasionally be palpable; however, they may also be associated with abruption and preterm labour, so caution should be exercised to ensure that women with fibroids are not having an abruption.Point tenderness on palpation over the location of the fibroid, particularly when there is no bleeding, will make abruption unlikely.
Fibroids can generally be identified on sonography.

Placenta praevia

Normal labour
Bleeding is not usually severe and is darker.The fetus is not compromised.Labour progresses normally.
The diagnosis is usually made clinically.Ultrasound will be normal.
Placental abruption
Usually painful.If the abruption is large, the uterus is rock-hard and the fetus will usually be compromised.Vaginal bleeding may range from absent to severe. Placental abruption may co-exist with placenta praevia. [46] [47]
Ultrasound may show abruption.
Miscarriage
More common in early pregnancy (i.e., first and early second trimester).There is usually crampy abdominal pain as bleeding becomes heavier.Placental abruption may co-exist with miscarriage.
The diagnosis is usually made clinically.Ultrasound may show products of conception.

Plantar fasciitis

Plantar fascia rupture
History of trauma, ecchymosis, and significant oedema around the heel and proximal arch. [3]
Ultrasound and MRI will show partial or total rupture of the plantar fascia instead of thickening. [21]
Inferior calcaneal bursitis
Pain with palpation to the inferior central heel.Tenderness found more proximally than with plantar fasciitis.Negative Windlass test.Fluctuant well-defined mass at the inferior central heel. [3]No pain with ankle, metatarsophalangeal joint extension dorsiflexion.
No differentiating tests.
Calcaneal contusion
Minimal pain with palpation of the plantar heel and non-specific findings on physical examination.May be no differentiating signs or symptoms apart from a history of preceding trauma.
MRI will show marrow oedema on short T1 inversion recovery and T2-weighted images and an ill-defined focal low signal on T1. [23]
Abductor hallucis tendonitis
Targeted pain with palpation and percussion of the abductor hallucis muscle belly.Pain with abduction and adduction of the hallux.
Oedema within the muscle belly or tendon or adjacent to the muscle fibres is found on MRI or ultrasound images.
Baxter's neuritis
Paraesthesia with percussion of the lateral plantar nerve. [3] [17]Pain is often described as burning in nature and unlike plantar fasciitis pain; may be present at rest.
No differentiating tests.
Calcaneal stress fracture
Pain with lateral compression of the heel is greater than inferior heel pain. [3] [14]
Radiolucent line transecting the calcaneal tuber from the rest of the calcaneal body on plain x-ray films, although x-rays can be negative initially with occult fracture.MRI shows low-signal intensity on T1 and T2 images with surrounding oedema. [23]
Medial calcaneal nerve entrapment
Paraesthesia with percussion of the tibial or the medial calcaneal nerve. [3] [14]Pain is often described as burning in nature and, unlike plantar fasciitis pain, may be present at rest.
No differentiating tests usually performed.
Rheumatoid arthritis
Typically bilaterally symmetrical presentation with erythema and oedema about the heels. [6]Pain and inflammation in other joints, especially smaller joints, with a symmetric presentation.
Rheumatoid factor 1:60 or more.Calcaneal erosive changes in the absence of infection on x-ray. [6]
Other inflammatory arthropathy (e.g., ankylosing spondylitis, Reiter's disease)
Erythema and oedema about the heel.May have associated back pain. [3] [6]Pain more commonly bilateral, although unilateral pain may occur.
Often, but not always, HLA-B27 positive.Oligoarthritis involving larger asymmetric joints on x-ray; x-ray presentation of enthesopathy. [6]
Sacroiliac nerve entrapment
Pain of the plantar proximal heel.Extending the knee and lifting the leg, with the patient supine, will incite low back pain.
MRI may demonstrate intervertebral disc disease.

Pleural effusion

Pleural thickening
Patient has a history of prior pleural disease such as TB or empyema, or exposure to environmental agents.
Thickened pleura from pleural fibrosis resulting from previous pleural inflammation, or prior environmental exposures such as asbestos, beryllium, and silica, can appear similar to a pleural effusion on CXR.
Pulmonary collapse and consolidation
History to support a possible underlying cause, such as haemoptysis and weight loss in lung cancer.
Can occur in conjunction with the pleural effusion from compression or can be mistaken for a pleural effusion on CXR. CT scan or ultrasound can more clearly define the difference between lung collapse and effusion.
Elevated hemidiaphragm
Can result from paralysis of the phrenic nerve.Paradoxical chest movement during the respiratory cycle can be a clue to diagnosis.
A fluoroscopic test to analyse diaphragmatic movement with rapid breathing (often called a 'sniff test') can evaluate diaphragm paralysis.
Pleural tumours/extrapleural fat
Extrapleural fat is asymptomatic.
The density of fat is much lower than that of fluid on CT scan and should be readily differentiated.Pleural tumours can also be easily demonstrated on CT.The presence of nodularity is often key to a malignant process. [17]

Pneumoconiosis

Asbestosis
History of exposure to asbestos. In certain workplaces, such as foundries and mines, workers may be exposed to both silica and asbestos. [18] The clinical presentation may be similar.
CXR appearance of asbestosis: there is lower zone linear interstitial fibrosis, View image progressively involving the entire lung, with pleural thickening. View imageCXR appearance of silicosis: there are small rounded opacities, initially beginning in the upper lobes, View image and with progression, these smaller nodules conglomerate into large opacities (progressive massive fibrosis). View image Unlike in asbestos exposure, there are no pleural changes seen on CXR, although pleural fibrosis may be seen from a pathological specimen of silicosis.Lung biopsy in patients with asbestosis will not show silicotic nodules, which are pathognomonic for silicosis.Some patients with exposure to asbestos and silica may have radiographic and or pathological changes of mixed dust.
Idiopathic pulmonary fibrosis
Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal.May be no other differentiating signs and symptoms.
Imaging (CXR or high-resolution CT scan [HRCT]) shows lower lobe linear fibrosis.There is a negative beryllium lymphocyte proliferation test (BeLPT).Lung biopsy does not show increased mineral content.
Sarcoidosis
Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal.There may be no other differentiating signs and symptoms. Although sarcoidosis may also involve non-respiratory organs, this is uncommon in people presenting with pneumoconiosis.
Imaging (CXR or HRCT scan) shows hilar lymphadenopathy and predominantly linear, not rounded, upper lobe scarring. View imageMay be associated with hypercalcaemia.Granulomas demonstrated on lung biopsy (granulomas also present in chronic beryllium disease).There is a negative BeLPT.
Rheumatoid arthritis
Although patients may have rheumatoid arthritis without pneumoconiosis, the diagnosis is sometimes mixed. Patients with pneumoconiosis may uncommonly develop rheumatoid arthritis or connective-tissue disease. Also, patients with a history of rheumatoid arthritis may develop pulmonary fibrosis.Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal in patients with rheumatoid arthritis without pneumoconiosis.Specific signs and symptoms of arthritis, rheumatoid nodules, pleuritis, pericarditis, and inflammatory eye disease may be present in people with rheumatoid arthritis, but not in people with pneumoconiosis that is not complicated by connective-tissue disease.
Lung biopsy does not show pathology of pneumoconiosis or increased mineral content in people with rheumatoid arthritis without pneumoconiosis.Immunological markers, such as rheumatoid factor (RF), are non-specific and may be present in patients with silicosis and coal workers' pneumoconiosis without connective-tissue disease, thus are not differentiating tests. [11] [19]Smooth rounded opacities may be seen on the CXR in people with silicosis or coal workers' pneumoconiosis who also develop rheumatoid arthritis (Caplan's syndrome). [7] [8] The opacities seen in Caplan's syndrome are smooth and typically golf-ball size. They differ from the opacities seen in progressive massive fibrosis (PMF), which have irregular borders. PMF may occur as coal workers' pneumoconiosis or silicosis progress. As the opacities of PMF increase in size, they may occupy the whole upper lobe and cause distortion in the lung structure.
Scleroderma
Although patients may have scleroderma without pneumoconiosis, the diagnosis is sometimes mixed. Patients with pneumoconiosis may uncommonly develop rheumatoid arthritis, connective-tissue disease, or vasculitides. Also, patients with a history of scleroderma may develop pulmonary fibrosis.Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal in patients with scleroderma without pneumoconiosis.Specific signs and symptoms of Raynaud's phenomenon, View image digital pits or ulcers, sclerodactyly, View image heartburn, reflux, or arthralgia may be present in people with scleroderma, but not in people with pneumoconiosis that is not complicated by connective-tissue disease.
Lung biopsy does not show pathology of pneumoconiosis or increased mineral content in patients with scleroderma without pneumoconiosis.Immunological markers, such as antinuclear antibody (ANA), are non-specific and may be present in patients with silicosis and coal workers' pneumoconiosis without connective-tissue disease, thus are not differentiating tests. [11] [19]
SLE
Patients with a history of SLE may develop pulmonary fibrosis, making a clear diagnosis sometimes more difficult.Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal.Specific signs and symptoms of malar, discoid, or photosensitive rash; arthritis; Raynaud's phenomenon; View image hypertension; oedema; or abdominal pain may be present in people with SLE, but not in people with pneumoconiosis that is not complicated by connective-tissue disease.
Lung biopsy does not show pathology of pneumoconiosis or increased mineral content.Immunological markers, such as antinuclear antibody (ANA), are non-specific and may be present in patients with silicosis and coal workers' pneumoconiosis without connective-tissue disease, thus are not differentiating tests. [11] [19]
Drug- or radiation-induced pulmonary fibrosis
History of medications such as amiodarone, nitrofurantoin, methotrexate, bleomycin, and cyclophosphamide, or history of receiving radiotherapy.Complete work-up and environmental history reveals an absence of history of significant exposure to mineral dust or metal.May be no other differentiating signs and symptoms.
Imaging (CXR or high-resolution CT scan) shows lower lobe linear fibrosis.There is a negative BeLPT.Lung biopsy does not show increased mineral content.
COPD
COPD not from pneumoconiosis is no different from COPD from pneumoconiosis, except that there will be a history of prolonged exposure to a mineral dust or metal when such an exposure is a significant contributing factor.
There are typically no distinguishing tests. If lung tissue is available, the dust/mineral content can be determined and quantified to identify exposures not identified in the exposure history, or to confirm the exposures that were identified from the history.

Pneumocystis jirovecii pneumonia

Bacterial pneumonia
Onset of symptoms is more rapid and acute than Pneumocystis pneumonia (PCP).Patients with bacterial pneumonia often have focal lung findings, purulent sputum, and chest pain.
Chest x-ray typically shows an alveolar pattern in a focal segment or lobar distribution.Bacterial pneumonia can occur with any CD4 cell count.Blood and sputum cultures may help determine aetiology.Aetiological agent is most often Streptococcus pneumoniae.Bronchoalveolar lavage (BAL), sputum, or tissue biopsy is negative for Pneumocystis jirovecii.
Coccidioidomycosis
Patients typically have travel history to areas of California, Arizona, New Mexico, south-western Texas, or southern parts of Utah and Nevada.Usually present with an influenza-like syndrome, chest pain, and dyspnoea.There may be skin findings of erythema nodosum or erythema multiforme.
Coccidioidomycosis can be diagnosed with serological testing, skin testing, culture positivity from appropriate samples, or histopathology that shows typical characteristic spherules in tissue samples. [72]Chest x-ray may show interstitial pneumonia similar to PCP but may have single or multiple nodules, thin-walled cavities, or hilar or mediastinal lymphadenopathy. [72]
Cytomegalovirus (CMV)
The presentation can be similar. CMV pneumonitis is usually associated with a non-productive cough and minimal findings on lung examination. [73]CMV pneumonitis is more common in HIV-negative patients than in those with HIV.
CMV pneumonitis is typically associated with CMV viraemia. Tests for diagnosis include: viral culture, serology, pp65 antigenaemia test, histopathology, and nucleic acid amplification and detection systems, most commonly PCR.Tissue biopsy with CMV-positive histology may suggest invasive disease. [73]
Histoplasmosis
Similar to PCP, patients may present with several weeks of fever and malaise but there may also be weight loss.Examination findings include hepatomegaly, splenomegaly and generalised lymphadenopathy. In some disseminated cases, patients can present with septicaemia, hypotension, disseminated intravascular coagulation, acute respiratory distress syndrome, liver failure, or renal failure.Unlike PCP, which rarely has extrapulmonary involvement, histoplasmosis may present with skin manifestations, neurological involvement, GI involvement, and adrenal insufficiency. [74]
Culturing the organism from an appropriate source is diagnostic but can take up to 4 weeks.Serological testing is limited in immunocompromised patients, who may not make antibodies. Antigen detection from appropriate samples can be a rapid and sensitive diagnostic test; however, false positives can occur with Blastomycosis, Paracoccidioidomycosis, and Penicillium marneffei infections.Fungal staining is rapid but is not a sensitive test. [74]
Kaposi's sarcoma lung involvement
Symptoms can include dyspnoea, fatigue, wheezing, and haemoptysis.May be associated with large pleural effusions. [75]Often associated with skin lesions.
High-resolution computed tomography (HRCT) of the chest may show nodules >1 cm in a bronchovascular distribution.Bronchoscopy shows typical pigmented lesions in the airways.Histopathology shows atypical spindle cells and vasoformative areas.Biopsy for Kaposi's sarcoma may be associated with an increased risk of bleeding and is generally not necessary.
Lymphocytic interstitial pneumonitis
Symptoms include progressive dyspnoea, non-productive cough, and fevers.More common in HIV-positive children than adults.
HRCT shows an interstitial pattern.Can occur with any CD4 cell count.Diagnosis may require an open lung biopsy, in which case tissue is negative for Pneumocystis jirovecii.
Mycobacterium avium complex (MAC)
Pulmonary MAC is uncommon in HIV-positive subjects and more often presents with extrapulmonary manifestations.
HRCT may show a bronchiolitis pattern.CD4 cell count is often low as <100 cells/microlitre.Blood or sputum culture is positive for Mycobacterium avium intracellulare.BAL, sputum, or tissue biopsy is negative for histochemical staining of Pneumocystis jirovecii.
Non-infectious interstitial lung disease
Typical symptoms are dyspnoea and fatigue.Fever is atypical.Onset is indolent over months to years.
HRCT findings may be helpful and show fibrosis and a peripheral distribution of abnormalities. These findings would be atypical for PCP.May require open lung biopsy to provide a tissue diagnosis.
Penicilliosis
Caused by Penicillium marneffei . Once considered rare, its occurrence has increased as a result of AIDS. It is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of South-east Asia.Typically, patients have a travel history to endemic areas of South-east Asia and the southern part of China.Can present with skin lesions, subcutaneous nodules, haemoptysis, anaemia, lymphadenopathy, and hepatomegaly.
Similar to PCP, radiography may show cavitary lung lesions.Diagnosis is by identification of the fungus in a clinical specimen.BAL, sputum, or tissue biopsy is negative for Pneumocystis jirovecii.
Pulmonary tuberculosis
Presentation can vary widely depending on the level of immunocompetency.May co-exist with PCP in HIV-positive patients.Symptoms can be present for weeks to months.
Acid-fast bacillus (AFB) staining and culture of respiratory or other specimens, if positive, is definitive for TB.BAL, sputum, or tissue biopsy is negative for Pneumocystis jirovecii.
Legionella
Legionnaires disease may also be characterised by a fever with non-productive cough and few pulmonary symptoms.Infected patients may also have diarrhoea, bradycardia, and abdominal pain.
Legionella pneumophila is the most common clinical type. Serology is diagnostic with acute IgG, IgM, or IgA titres. AST and ALT may be elevated.
Cryptococcus
Causes pulmonary, neurological, and disseminated disease and pedunculated skin lesions.CNS manifestations are more suggestive of cryptococcosis than PCP.
Peripheral and CSF cryptococcal serology are sensitive and specific tests.BAL, sputum, or tissue biopsy is negative for Pneumocystis jirovecii.
Blastomycosis
Blastomyces dermatitidis is endemic to North America and is a fungal organism present in soil.There may be a history of contact with infected dogs or cats.Presents with systemic symptoms of fever and with pneumonia.Skin lesions are widespread, ulcerated with typical pustules around the margin.
Characteristic broad-based, budding fungal organisms in sputum or tissues by cytology or histology.BAL, sputum, or tissue biopsy is negative for Pneumocystis jirovecii.
Sarcoidosis
May present with similar symptoms to PCP but also with systemic involvement, including skin nodules.
Bilateral hilar lymphadenopathy on chest x-ray.Lung biopsy demonstrates granulomatous tissue.
Mycoplasma pneumoniae
Respiratory infection occurs mainly in children and young adults and is often seen in close community settings, such as boarding schools, colleges, and military bases.There is a relative increase in incidence in the late summer or autumn and epidemics often occur at 3- to 5-year intervals.
Microbiology and culture of Mycoplasma pneumoniae from either nasopharyngeal aspirate or sputum or throat swabs. Not widely available.Rise in serum titre of Mycoplasma-specific Ig on convalescent serum. The amount of titre change is dependent on the commercial assay used.
Pulmonary embolus
History of deep-vein thrombosis may be present.Symptoms include chest pain and dyspnoea.Syncope may be present.Signs include tachypnoea (respiratory rate >16 breaths per minute), fever >37.8°C (100.0°F), and increased heart rate (>100 bpm).
Definitive diagnostic modalities of exclusion/confirmation include D-dimer, multi-detector computed tomography (MDCT) of chest, V/Q scan, and pulmonary angiography.
Viral pneumonia
Symptoms and signs may be similar to PCP. Lack of effectiveness of antibiotics.
Positive nasopharyngeal viral cultures.Relative lymphocytosis in WBC.
Influenza
Symptoms and signs may be similar to PCP.Lack of effectiveness of antibiotics.
Viral serology or culture may be positive for influenza.
Acute respiratory distress syndrome (ARDS)
History of aspiration, inhalation injury, acute pancreatitis, trauma, burns, pulmonary contusion, transfusion-related lung injury, cardiopulmonary bypass, fat embolism, disseminated intravascular coagulation, and drug overdose.On physical examination, patients with ARDS have acute hypoxic respiratory failure requiring high levels of oxygen and/or PEEP to maintain oxygen saturation >90%.Lung examination may reveal basilar or diffuse rales.ARDS may also complicate PCP and both conditions may co-exist.
Blood, sputum, and urine cultures and lipase tests are done to test for underlying infection and pancreatitis.BAL or tracheal aspirate is recommended in patients with ARDS due to suspected pneumonia and those without a defined predisposing condition. BAL can be tested for the presence of Pneumoncystis jirovecii.

Pneumothorax

Asthma, acute exacerbation
Expiratory wheeze and chest tightness. [34]
Therapeutic trial of bronchodilators relieves symptoms.
COPD, acute exacerbation
Fever, increased cough, and change in sputum colour suggest an infective exacerbation. Bullous pulmonary disease may, however, be clinically indistinguishable from pneumothorax. [34]
CT of the chest may be necessary to differentiate a pneumothorax from a pulmonary bulla. [29]
Pulmonary embolism
Presence of risk factors for thromboembolism, such as obesity, prolonged bed rest, pregnancy/postpartum period, inherited thrombophilias, active malignancy, recent trauma/fracture, and a history of previous thrombosis. Physical examination abnormalities suggestive of deep venous thrombosis are present in 50% of patients. [2]
The chest x-ray is most commonly normal, but pulmonary vascular oligaemia and atelectasis may be present. Pulmonary infiltrates may develop and can be of any shape, not just wedge-shaped.CT pulmonary angiogram with direct visualisation of thrombus in a pulmonary artery.Ventilation-perfusion scan (V/Q scan) with an area of ventilation that is not perfused.
Myocardial ischaemia
Typically the patient complains of chest tightness and shortness of breath that is brought on by exertion. The chest discomfort is usually substernal and is described as a pressure sensation. Pain may radiate into the neck and down the arms. Nausea, vomiting, and diaphoresis may accompany the chest discomfort.
An ECG may demonstrate ischaemia or injury patterns.Serum levels of CK-MB and troponin increase when myocardial infarction has occurred.
Pleural effusion
Patients will experience pain. However, as fluid accumulates in the pleural space, the visceral and parietal pleura will move apart and chest pain will ease. Physical examination demonstrates decreased fremitus, dullness to percussion, and decreased breath sounds. As pleural fluid accumulates, the patient may experience shortness of breath.
A chest x-ray is typically diagnostic of a pleural effusion. A meniscus sign at the costophrenic angle in an upright chest x-ray is diagnostic. Between 250 and 500 mL of pleural fluid is necessary to visualise effusion by chest x-rays.CT scans are more sensitive and may give additional clues to the clinician concerning the aetiology of the pleural fluid.
Bronchopleural fistula
A bronchopleural fistula is a communication between the pleural space and the bronchial tree that persists for 24 hours or more. The most common cause is postoperative complication of pulmonary resections. Other aetiologies include lung necrosis complicating infection, persistent spontaneous pneumothorax, chemotherapy or radiotherapy for bronchogenic carcinoma and metastatic cancer to the lung, and tuberculosis.The presentation is characterised by sudden appearance of dyspnoea, hypotension, subcutaneous emphysema, cough, and purulent sputum, and shifting of the trachea and mediastinum. [35]
The diagnosis is established by placing a chest tube or small-bore catheter into a pneumothorax and demonstrating a persistent air leak.
Fibrosing lung disease
Patients typically complain of slowly progressive dyspnoea. Crackles are present on auscultation of the chest. A prominent second heart sound may also be evident. The patient may have digital clubbing.
A chest x-ray is often the initial radiological examination when fibrotic lung disease is suspected.CT scanning, however, is more sensitive and helps in determining whether there is an active inflammatory disease of the lung. A ground-glass infiltrate indicates that alveolitis is present.Further diagnostic studies and therapeutic interventions may be necessary.
Oesophageal perforation
Oesophageal perforations most commonly occur after medical instrumentation or para-oesophageal surgery, and following sudden increase in intra-oesophageal pressure combined with negative intrathoracic pressure caused by straining or vomiting (Boerhaave's syndrome).Patients complain of severe retrosternal chest and upper abdominal pain. Odynophagia, tachypnoea, dyspnoea, cyanosis, fever, and shock develop rapidly thereafter. The physical examination is usually not helpful, particularly early in the course. Subcutaneous emphysema (crepitation) is an important diagnostic finding but is not very sensitive. A pleural effusion with or without a pneumothorax may be present.
Plain chest radiography is almost always abnormal in oesophageal rupture. Early, the diagnosis is suggested by mediastinal or free peritoneal air. Later widening of the mediastinum, subcutaneous emphysema, and pleural effusion with or without a pneumothorax may develop. CT scan may demonstrate oesophageal wall oedema and thickening, extra-oesophageal air, peri-oesophageal fluid with or without gas bubbles, mediastinal widening, and air and fluid in the pleural spaces and the retroperitoneum.The diagnosis can also be confirmed by water-soluble contrast oesophagram, which reveals the location and extent of extravasation of contrast material.
Giant bullae
Patient's complaints and physical examination may mimic those of a pneumothorax. Patient may also present with acute dyspnoea due to another cause such as an exacerbation of COPD.
A giant bulla is defined as a bulla that occupies one third or more of the ipsilateral hemithorax and develops slowly over time. However, if there are no old x-rays available for comparison, then differentiation from a pneumothorax may be impossible. Faint radiopaque lines within the bulla may be the only clue that the abnormality seen on the chest x-ray is not a pneumothorax.Since placement of a chest tube into a giant bulla can have deleterious results, a CT scan of the chest should be obtained to help make the differentiation between both diagnoses.

Poliovirus infection

Viral gastroenteritis in adults
Essentially indistinguishable on clinical grounds from the minor illness of poliovirus infection. [1] [2]
Viral gastroenteritis may be caused by a variety of enteroviruses. [9] Stool testing with PCR should reveal the aetiology of the condition. [1] Stool culture will be negative for poliovirus.
Transverse myelitis
Usually symmetrical motor and sensory loss below the level of the spinal cord lesion. Approximately one third of patients report a febrile illness preceding the symptoms.
MRI usually shows spinal cord inflammation and focal demyelination. [1]CSF analysis usually shows elevated protein. Viral cultures should be negative for poliovirus.
Guillain-Barre syndrome (GBS)
Similar, in that it may also be preceded by viral syndrome such as gastroenteritis. However, any limb weakness is usually symmetrical, and cranial nerve weakness may be present as well. Other differentiating symptoms include those of autonomic dysfunction, which are not typical of poliomyelitis.
Typical CSF findings include albumin-cytological dissociation: an elevated protein level (1 to 10 g/L [100 to 1000 mg/dL or 0.1 to 1 g/dL]) without an accompanying increased cell count. A sustained increased WBC count may indicate an alternative diagnosis such as infection.Viral cultures should be negative for poliovirus.Serological and stool testing may show evidence of recent Campylobacter jejuni infection (up to 40% of GBS patients).Electrodiagnostics (electromyography and nerve conduction studies) may show prolonged distal latencies, conduction slowing, and conduction block.
Encephalitis
Does not usually result in unilateral paralysis and muscle atrophy; may have features not associated with poliomyelitis, such as mental status changes, fevers, and seizures.
Viral encephalitis may be caused by a variety of enteroviruses including echovirus, coxsackievirus, poliovirus, and enterovirus-71. [9] CSF testing with PCR should reveal the aetiology of the condition. [1]
Leprosy
Chronic infectious disease affecting children and young adults in endemic areas; involves peripheral nerves, resulting in loss of sensation, weakness, and muscle wasting.Nerve thickening and skin lesions distinguish leprosy from poliomyelitis.
Skin scraping, skin or nerve biopsy, and histopathology show granulomas and acid-fast bacilli (AFBs).
Tetanus infection
History of wound infection. Non-immunised and immunosuppressed children and adults are most susceptible.Life-threatening neurological symptoms include muscle spasms, restlessness, irritability, dysphagia, opisthotonus, and seizures, as well as respiratory failure due to powerful contraction of the intercostal muscles or involvement of the glottis or diaphragm. Severe autonomic dysfunction may arise after several days.
Caused by the exotoxin of Clostridium tetani, a gram-positive, spore-forming obligate anaerobic bacillus. The spores of the organism may be detected within the wound.Tetanus toxin can be detected in serum, confirming a clinical diagnosis. Samples must be collected prior to immunoglobulin treatment. Absence of toxin in the serum does not exclude the clinical diagnosis.
Rabies
There is usually a history of animal bite, but as the incubation period may be several months, the history may be unclear. Symptoms begin with fever, malaise, and headache, and then progress to seizures, inability to swallow (water), and coma. Death is from respiratory insufficiency.
Rabies is a viral zoonotic infection that causes encephalitis in mammals. The virus travels from the peripheral nervous system.Rabies infection is diagnosed by performing PCR or viral culture on skin samples taken before death, or on brain samples taken after death. It is also possible to make the diagnosis from saliva, urine, and CSF samples, but this is not as sensitive.Inclusion bodies called Negri bodies may be found in infected tissues on histopathology.
Botulism
Toxin ingestion, usually from contaminated food, leads to a clinical syndrome characterised by cranial nerve palsies, oculobulbar weakness, and descending, symmetrical flaccid paralysis in the absence of fever. Affected patients do not complain of sensory deficits. Children are most susceptible.Descending symmetrical paralysis affects the voluntary muscles of the neck, shoulders, and upper extremities, followed by the proximal and distal lower extremities.
Caused by the exotoxin of Clostridium botulinum, a large, gram-positive anaerobic bacillus. The toxin may be identified in serum, stool, and gastric samples, or in contaminated food.
Aseptic meningitis
Headache, neck stiffness, and fever with no altered mental status (maybe mild somnolence) and focal neurological signs.Frequently meningitis and encephalitis co-exist.May be difficult to distinguish from non-paralytic poliovirus infection.
MRI shows evidence of meningeal enhancement, with no evidence of brain parenchymal involvement.
HIV-related myelopathy
Signs and symptoms referable to the spinal cord lesions, including paraparesis, often accompanied by spasticity or ataxia (or both) coupled with dementia.
ELISA testing should be ordered when HIV testing is indicated. False negatives may occur during a window period immediately after infection and before antibodies to HIV have developed. A positive result should be confirmed with a Western blot or a second ELISA. The window period can be reduced to 2 to 4 weeks by using fourth-generation tests and those that include IgM antibodies to HIV.CSF, microbiological, and spinal imaging studies are inconclusive or unspecific.
Amyotrophic lateral sclerosis (ALS)
Approximately 60% of ALS patients experience muscle weakness and stiffness as the initial symptom. Examination also reveals muscle atrophy and rigidity. Peripheral hyper-reflexia is often present, which is not typical for poliomyelitis.
Electromyography (EMG) testing is a significant part of the diagnosis of ALS. The current criteria define a positive EMG when signs of active denervation include fibrillation potentials and positive sharp waves, with fasciculation potentials.
Multiple sclerosis
Neurological manifestations of poliomyelitis can mimic clinical symptoms of multiple sclerosis, but in almost all cases of multiple sclerosis there are also brain lesions.Multiple sclerosis has a more variable presentation, with multiple episodes separated by space (i.e., neurological symptoms result from lesions in different CNS sites) and time. Symptoms may include progressive limb weakness, gait difficulty, ataxia, loss of balance, paroxysmal vertigo.
Brain MRI typically shows areas of demyelination.CSF examination shows raised IgG and oligoclonal banding.
Peripheral neuropathy
Compression neuropathies and neuropathies due to metabolic disease, drugs, or toxins may be difficult to differentiate from neurological symptoms of poliomyelitis.
Nerve conduction studies and EMG are helpful in confirming neuropathy and characterising the neuropathy (i.e., demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy).

Polyarteritis nodosa

Granulomatosis with polyangiitis (Wegener's)
Granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) are forms of ANCA -associated small-vessel vasculitis, whereas polyarteritis nodosa (PAN) affects only medium-sized vessels (i.e., small- and medium-sized arteries).Commonly presents with signs and/or symptoms involving the upper or lower respiratory tract.Glomerulonephritis and pulmonary capillaritis are features of ANCA -associated vasculitis conditions but are not found in PAN.
ANCA: cANCA (cytoplasmic pattern on immunofluorescence testing) combined with positive proteinase 3 antibody testing by enzyme immunoassay (EIA); pANCA (perinuclear pattern on immunofluorescence testing) combined with positive myeloperoxidase antibody testing by EIA. ANCA is not associated with PAN.Urinalysis: may show haematuria, proteinuria; dysmorphic red blood cells, RBC casts.Pulmonary function testing: typically be normal or may show evidence of extrathoracic airway obstruction in cases of subglottic stenosis.CT chest: lung nodules (which may cavitate); infiltrates.Tissue biopsy (skin, lung, kidney): granulomatous inflammation, necrosis and vasculitis; minimal/absent immune deposits on immunofluorescence and electron microscopy.
Microscopic polyangiitis
Granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) are forms of ANCA -associated small-vessel vasculitis, whereas polyarteritis nodosa (PAN) affects only medium-sized vessels (i.e., small- and medium-sized arteries).MPA and GPA seem to be part of a clinical spectrum. However, the upper respiratory tract is not involved in MPA.Glomerulonephritis and pulmonary capillaritis are features of ANCA -associated vasculitis conditions but are not found in PAN.
ANCA: positive pANCA (perinuclear) more common than cANCA (cytoplasmic). ANCA is not associated with PAN.Urinalysis: may show haematuria, proteinuria; dysmorphic red blood cells, RBC casts.CT chest: alveolar haemorrhage.Tissue biopsy (skin, lung, kidney): absence of granulomatous inflammation.
Churg-Strauss syndrome
Granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) are forms of ANCA -associated small-vessel vasculitis, whereas polyarteritis nodosa (PAN) affects only medium-sized vessels (i.e., small- and medium-sized arteries).Patients typically present with a history of asthma, allergic rhinitis, or sinusitis.Peripheral neuropathy (typically mononeuritis multiplex) is the most common vasculitic manifestation.Glomerulonephritis and pulmonary capillaritis are features of ANCA -associated vasculitis conditions but are not found in PAN.
FBC: significant (>10% of peripheral WBC count) peripheral eosinophilia.Urinalysis: may show haematuria, proteinuria; dysmorphic red blood cells, RBC casts.ANCA: usually pANCA (perinuclear). ANCA is not associated with PAN.Tissue biopsy (sural nerve, skin): granulomatous inflammation, may have extravasated eosinophils.
Giant cell arteritis (GCA)
Giant cell arteritis (GCA) does not usually present with mononeuritis multiplex, orchitis, or coronary vasculitis, nor does it involve the skin or affect the renal arteries.GCA is predominantly a large- and medium-sized vessel vasculitis with a predilection for the cranial arteries. It is associated with temporal arteritis, though the temporal artery can also be involved in PAN, and PAN can cause ischaemic optic neuropathy similar to that seen in GCA.
Magnetic resonance, CT, or conventional angiography shows affected medium-sized cranial vessels, especially the temporal artery. GCA also affects extracranial large vessels, such as the aorta and the carotid arteries, but extra-cranial medium-sized arteritis is more likely to be due to PAN.
Infection
Endovascular bacterial infection is an important vasculitis mimic that needs to be excluded before immunosuppressive therapy can be started.HIV and hepatitis C virus (HCV) are associated with causing vasculitis in their own right. [43] HCV-related vasculitis is usually in the form of a cryoglobulinaemia.Epstein-Barr virus, cytomegalovirus, parvovirus, and many other viruses are implicated in causing vasculitis or can cause symptoms that mimic vasculitis. [43]
Blood cultures to detect bacteraemia. HIV serology, HCV serology, or other viral serology when clinically appropriate to detect infection. The presence of cryoglobulins suggests an HCV-related vasculitis.
Rheumatoid arthritis
This can present with similar symptoms to those of PAN or cause a secondary vasculitis. A presentation with mainly arthritis should lead to investigations for rheumatoid arthritis.
Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP antibodies) are positive in rheumatoid arthritis.
Systemic lupus erythematosus (SLE)
SLE can present with similar symptoms to those of PAN or cause a secondary vasculitis. A malar rash, alopecia, oral ulcers, or serositis, especially in a young woman, should trigger investigation for SLE.
ANA is positive in SLE. Anti-double-stranded DNA antibodies (anti-dsDNA) can be useful to make a diagnosis of SLE if the clinical manifestations fit with this diagnosis.
Malignancy
Fever, weight loss, fatigue, myalgia, and arthralgia may be due to cancer. In the absence of organ involvement characteristic of vasculitis, a thorough evaluation for malignancy should be performed.Vasculitis can occur as a paraneoplastic phenomenon, particularly with haematological malignancies. [44]
Investigation for malignancy should be guided by specifics of history and examination. This may involve checking tumour markers, imaging of chest/abdomen/pelvis, and other investigations as clinically appropriate.
Fibromuscular dysplasia (FMD)
FMD can affect the renal, carotid, mesenteric, and other visceral arteries. Ischaemic symptoms, depending on the arterial system involved, result from luminal narrowing. However, FMD does not cause fever, weight loss, arthritis, skin lesions, or mononeuritis multiplex.
Biopsy is usually difficult, so imaging with conventional digital subtraction angiography remains the best method of diagnosis. This shows a 'string of beads' with aneurysms and stenosis.Angiographic findings are sometimes indistinguishable from those of PAN, [45] but magnetic resonance angiography may show the appearance of a 'string of beads' with thickening of the vessel wall.Inflammatory markers (CRP or ESR) are not raised in FMD.
Atheroma
Atherosclerosis is the most common cause of organ ischaemia. Symptoms and signs depend on the arterial systems involved. Atheroma formation is accelerated in inflammatory diseases, including PAN, in which a combination of inflammation and ischaemia may both be present, making it difficult to differentiate between atherosclerotic disease and vasculitis.
Conventional digital subtraction angiography is the best test; the absence of microaneurysms in purely atherosclerotic disease is the main discriminating factor.CRP and ESR are not usually raised in patients with atherosclerosis alone.
Cholesterol emboli
Usually presents with distal ischaemia, hypertension, and renal impairment, but can manifest itself with any ischaemic symptom, including mononeuropathy. [46]Typically occurs after a vascular interventional procedure causing mechanical disruption of an atheromatous plaque. Small cholesterol crystals shower downstream, or large plaques break off and occlude larger vessels. In the first scenario, the crystals induce an inflammatory reaction in small vessels, resulting in fibrosis and eventually tissue ischaemia. [47]
Biopsy of affected organ shows microcrystals of cholesterol.
Atrial myxoma
Can cause recurrent emboli to multiple organs, resulting in tissue ischaemia and infarction. Symptoms may mimic vasculitis. In some cases, this embolus is purely thrombus; in others, a combination of thrombus and tumour material. [48]
Echocardiography reveals the atrial mass.
Catastrophic antiphospholipid syndrome
A rare disorder with pathological overlap to antiphospholipid syndrome. It presents with multiorgan infarction from microthrombi over a period of days to weeks. Preceding infection is a risk factor. [49]
IgG anticardiolipin antibodies (IgG) and beta-2 glycoprotein are elevated.Lupus anticoagulant may be present.FBC may show a low platelet count, and the partial thromboplastin time may be raised.
Buerger's disease (thromboangiitis obliterans)
Typically occurs in men aged 20 to 40 years who are heavy smokers, but can occur in women and at older ages. Presents with claudication, ischaemic pain at rest, Raynaud's phenomenon, or gangrene of the extremities.
Pathologically, there is vasculitis affecting the small- and medium-sized vessels of the hands and feet. Angiogram of extremities and renal or mesenteric arteries shows occluded vessels distal to the elbow or knee, with a corkscrew appearance of collateral vessels. Differentiated from PAN by the absence of visceral vessel involvement. [50]

Polycystic kidney disease

Acquired cystic kidney disease
Clinical history is the most helpful discriminator.Occurs in the setting of pre-existing renal disease.
Kidney size and cysts are usually small, as opposed to enlarged kidneys usually seen in ADPKD; however, kidneys may increase in size and resemble those of ADPKD.Haemorrhage often seen on imaging.
Simple cyst
Common in adults. Incidence increases with age; tend to be uncommon in people <40 years of age.Absence of family history and not meeting the Ravine's criteria is helpful. [38]Rarely leads to significant pain, rupture, or infection.
Diagnosis made on ultrasound. Criteria include absence of internal echoes; strong, sharply defined distant wall with smooth distinct margins; acoustic enhancement; and a spherical or slightly ovoid shape.Bosniak's classification is used to classify renal cysts and defines appropriate management. [58] [59]
Tuberous sclerosis complex
Facial angiofibromas, forehead patches, shagreen patches, subungual fibromas, hypomelanotic macules, cortical tubers, subependymal nodules, giant cell astrocytomas, cardiac rhabdomyomas, and pulmonary lymphangioleiomyomatosis.
TSC1 and TSC2 gene mutation analysis.Commercial testing is available.Most frequent renal findings are angiomyolipomas, renal cysts, and renal cell carcinomas.
von Hippel-Lindau syndrome(VHL)
Renal cell carcinoma, retinal and/or central nervous system haemangioblastomas, phaeochromocytomas, pancreatic cysts, and epididymal cystadenoma.
VHL gene mutation analysis.Commercial testing is available.
Maturity-onset diabetes of the young type 5
Type 2 diabetes mellitus, renal cysts, and genital tract abnormalities. [60]
HNF1-beta gene mutation analysis.Commercial testing is available.
Medullary cystic kidney disease/uromodulin-associated kidney diseases
Chronic tubulointerstitial disease and frequent gout, with renal cysts at the corticomedullary junction.FHx of chronic kidney disease of unknown cause.
MRI of kidneys reveals renal cysts typically at the corticomedullary junction.Magnetic resonance urography shows a medullary nephrogram or a ring-shaped contrast enhancement along the base of the papillae. Thin-cut CT may also be helpful.UMOD gene mutation analysis (MCKD2), if positive, confirms diagnosis. However, there is a second disease locus for the MCKD1 locus; therefore, mutation analysis will not completely exclude medullary cystic kidney disease if negative.Commercial testing is available.
Orofacial digital syndrome type 1
PKD occurs in <50% of patients with orofacial digital syndrome type 1 (OFD1), which is a sex-linked disorder.Renal cysts can develop from tubules and glomeruli.Age of onset is most often in adulthood, but renal cysts in children have been described.
OFD1 gene mutation analysis.
Medullary sponge kidney
Characterised by tubular dilatation of the collecting ducts confined to the medullary pyramids.Absence of a family history of the disease.
Sparing of the cortex on CT or MRI.
Localised cystic disease
Small cysts localised to one portion of the kidney.Not a genetic disease. Family history is always absent.Not associated with renal failure.
Cystic disease is always unilateral.

Polycystic ovary syndrome

21-hydroxylase deficiency
Partial deficiency of the 21-hydroxylase enzyme within the cortisol biosynthetic pathway results in accumulation of androgenic precursors.Clinical presentation may be indistinguishable from that of PCOS.Certain ethnic groups are at risk: Yupik Eskimos, Ashkenazi Jews, and Hispanic, Italian, and Yugoslav women.Very rare in African-Americans.
A morning, follicular-phase 17-hydroxyprogesterone level <6 nanomol/L (<200 nanograms/dL) rules out the disorder. A value >24 nanomol/L (>800 nanograms/dL) rules it in. Intermediate values prompt cosyntropin (ACTH) stimulation testing.Patients with non-classic congenital adrenal hyperplasia always have a stimulated (60 minutes) 17-hydroxyprogesterone value >30 nanomol/L (>1000 nanograms/dL) (usually >45 and <303 nanomol/L or >1500 and <10,000 nanograms/dL).
Thyroid dysfunction
Thyroid dysfunction may lead to menstrual irregularities. However, unlike in most cases of PCOS, hyper-androgenism is absent.Clinical features of hypothyroidism (e.g., lethargy, cold intolerance) or hyperthyroidism (e.g., weight loss, nervousness, heat intolerance) may be present.
TSH level greater (primary hypothyroidism) or less than (hyperthyroidism) the normal range.
Hyperprolactinaemia
Hyperprolactinaemia may lead to infrequent or absent menses.Mild hyper-androgenic features may be observed.Galactorrhoea is usually present.There may be headache or visual field deficit.
Prolactin level greater than the upper limit of the normal range. However, some PCOS patients have prolactin levels that are slightly elevated. [2]
Cushing's syndrome
Circulating cortisol and androgen levels are elevated, resulting in obesity, hirsutism, acne, and menstrual irregularity.Usually with moon facies, central fat deposition, hypertension, muscle wasting, abdominal striae, and osteoporosis.Adrenal carcinomas in particular are inefficient at synthesising cortisol and can release large amounts of androgenic precursors, leading to severe hirsutism and virilisation.
Screen for Cushing's syndrome with 24-hour urinary free cortisol (normal <248 nanomol/24 hours [<90 micrograms/24 hours] for radio-immunoassay or <138 nanomol/24 hours [<50 microgram/24 hours] for high-performance liquid chromatography ) or low-dose dexamethasone suppression test (e.g., overnight: 1 mg at 11 p.m. or midnight), with 8 a.m. plasma cortisol the next morning. Normally a.m. cortisol is suppressed to <138 nanomol/L (<5 micrograms/dL) (<50 nanomol/L or <1.8 micrograms/dL with modern cortisol assays sensitive to detect 28 nanomol/L (1 microgram/dL)). An alternative screening test is late p.m. salivary cortisol.
Androgen-secreting neoplasms
These are steroid-producing tumours of the adrenal or ovary.Autonomous androgen production often produces rapid-onset (within months) progressive virilisation (frontal balding, severe hirsutism, increased muscle bulk, deepened voice, clitoromegaly).
A baseline total testosterone >6.9 nanomol/L (>200 nanograms/dL) (or free testosterone >0.7 nanomol/L [>2 nanograms/dL]) warrants ultrasound of the ovaries (but may miss small hilus cell tumour).Dehydroepiandrosterone sulphate (DHEAS) >7000 nanograms/mL should prompt CT scan of the adrenals.Some androgen-producing tumours may be associated with serum testosterone <6.9 nanomol/L (<200 nanograms/dL).Most women with testosterone >6.9 nanomol/L (>200 nanograms/dL) have PCOS or hyper-androgenism-insulin resistance acanthosis nigricans (HAIR-AN) syndrome. The rapidity of onset of virilisation (<2 years) or onset late in life is a better predictor of neoplasm than androgen levels. [47]
Syndromes of severe insulin resistance
Degrees of insulin resistance, hyperinsulinaemia, and hyper-androgenism tend to be more severe than in PCOS.Also known as HAIR-AN syndrome. View imageLipodystrophy may be present.
Diagnosis is based on fasting insulin >556 picomol/L (>80 micro-units/mL) and/or peak insulin >2084 picomol/L (>300 micro-units/mL) during a 3-hour 75-g oral glucose tolerance test, provided that beta cells are functional (reflected in normal glucose levels).
Androgenic/anabolic drugs
History of use or abuse of testosterone, anabolic steroids, danazol, dehydroepiandosterone (DHEA), androstenedione, 19-norprogestins, norgestrel, levonorgestrel, or norethisterone.Severity of hyper-androgenism varies depending on dose and duration of drug use.
Depending on agent used, blood evaluation for androgen levels may or may not be diagnostically useful.
Hypogonadotropic hypogonadism
Presents with oligo-anovulation, but hyper-androgenism is absent.
Low serum FSH and oestradiol.
Premature ovarian failure
Presents with anovulation, but hyper-androgenism is absent.
High serum FSH and low serum oestradiol.
Apparent cortisone reductase deficiency
Functional decrease in 11-beta-hydroxysteroid dehydrogenase type 1, leading to decreased conversion of inactive cortisone to cortisol.As a result of enhanced peripheral clearance of cortisol, there is less feedback suppression of ACTH, resulting in adrenal androgen excess.Clinically may be indistinguishable from PCOS. [48]
Ratio of tetrahydrocortisols to tetrahydrocortisone is very low (0.04 to 0.08, normally 0.5 to 2.0).Both adrenals often enlarged.Urinary free cortisol may appear elevated. [48]

Polycythaemia vera

Secondary polycythaemia due to hypoxia
History and examination suggest an underlying cause of hypoxia.Possible scenarios include smoking and sleep apnoea, but other causes of lung disease need to be considered.
Room air oxygen saturation <92% suggests significant hypoxia.ABG confirms the result.Overnight oximetry can be abnormal in people with sleep apnoea. However, it is questionable whether sleep apnoea alone is sufficient to produce an erythrocytosis without other contributing factors, so these people should be screened for other underlying lung disease as well.PFT (spirometry and diffusing capacity of the lung for carbon monoxide) is abnormal in people with underlying lung disease.Erythropoietin level is normal or elevated with secondary polycythaemia but usually low and occasionally normal in PV.
Essential thrombocytosis
Examination is frequently indistinguishable, although these patients do not have plethoric findings.
No test absolutely differentiates.Usually no history of elevated Hb.A normal erythropoietin, isolated thrombocytosis, and absence of elevated Hb concentration favour essential thrombocytosis.
Leukaemia, chronic myelogenous (CML)
May be clinically indistinguishable, although thrombosis is much less common with CML.
Screening for Philadelphia chromosome 9;22 translocation is almost always positive in CML.
Polycythaemia due to elevated erythropoietin level
There may be evidence of the presence of an erythropoietin-secreting tumour.There may be a family history of familial polycythaemias such as Chuvash polycythaemia.Patient may be receiving exogenous erythropoietin.
Imaging studies, as clinically appropriate following history and examination, may demonstrate erythropoietin-secreting tumour. The following may be abnormal: abdominal CT, MRI, or ultrasound; brain MRI or CT scan with contrast; CXR.
Polycythaemia due to testosterone excess
History of exogenous testosterone supplementation.
No other differentiating tests required following appropriate history.Unless there is a clear history that the polycythaemia only began with the initiation of testosterone, a trial period off testosterone to test if haemoglobin returns to normal can be done.
Congenital polycythaemia
Appropriate family history can be helpful but is not always revealing.Autosomal dominant history suggests erythropoietin receptor mutation, mutation of HIF2 alpha gene, or high-affinity Hb.Recessive history suggests Chuvash polycythaemia.
Specialised genetic tests will be positive for the particular congenital disorder present.

Polymorphous light eruption

Photo-allergic reaction
History of potential photo-allergic substances, both topical (e.g., UV filters, such as PABA [para-aminobenzoic acid], cinnamates, artificial scents) and systemic medicines, such as antidepressants, antihypertensive medicine, antiphlogistics, or antibiotics.Typical clinical signs include irregular erythema, papulovesicles, infiltration with scaling, and crusts.The clinical manifestation resembles that of an allergic contact dermatitis, but confined to UV-exposed areas. Some dissemination may occur. The typical symptom is itching. View image
Photo-patch testing demonstrates a delayed reaction, with a slowly increasing (crescendo) inflammatory/eczematous reaction.
Phototoxic reaction
Typical clinical signs are an amplified sunburn reaction and a positive history for phototoxic agents, both topical (e.g., tar, psoralens, giant hogweed, certain perfumes) and systemic medicines, such as antidepressants, diuretics, antiphlogistics, psoralens, or antibiotics (especially, tetracycline).Typical symptoms are stinging and burning, even pain. View imageIn PLE there is usually only itching.
Photo-patch testing demonstrates a sharply delineated, immediate, or delayed reaction, with a slowly decreasing (decrescendo) reaction.
Chronic actinic dermatitis
Persistent light reaction, actinic reticuloid, or chronic photosensitive dermatitis are synonyms. [37] [38] [39]Typically UV-B-induced (while PLE is more commonly UV-A-induced). Symptoms evolve over several days (like PLE), but persist for many weeks and form thick plaques, eczematous lesions with scaling and erosions, and lichenification. View image
Single photoprovocation on previously non-UV-exposed skin causes induction of a persistent dermatitis (within 72 hours).Skin biopsy and histopathological examination show spongiotic changes in the epidermis with uneven epidermal hyperplasia, crusts, and individual necrotic keratinocytes. The dermo-epidermal junction shows vacuolar alteration accompanied by a pronounced perivascular lymphocytic and sometimes also eosinophilic infiltration around the superficial and deep plexus.
Solar urticaria
Clinical signs consist of urticaria on UV-exposed sites that disappear quickly. The urticarial variant of PLE might resemble this presentation; however, skin lesions are visible for a few days in PLE.
Single photoprovocation on previously non-UV-exposed skin demonstrates immediate (up to 1 hour) induction of urticarial patches. Visible or infrared light might be part of the induction spectrum. If conventional tests are negative, exposure to natural sunlight may be considered. [40]
Erythema exudativum multiforme
Photosensitive variants of erythema exudativum multiforme are rare but difficult to distinguish from the erythema exudativum multiforme type of PLE. [4] Typically, a concurrent infection with herpes simplex virus is present together with intensive UV exposure, which elicits symptoms. [4]
Diagnosis is clinical
Systemic lupus erythematosus
Typical signs involve the delayed appearance of erythematous plaques on UV-exposed sites that persist over a prolonged period of time (weeks).Typical symptoms are stinging and burning. Skin lesions disappear within a few days (after avoiding UV exposure). View image
Repetitive photoprovocation on previously non-UV-exposed predilection sites (upper arms, shoulders). Induction of typical skin lesions might take time (several days up to 3 weeks) and require several weeks for remission. [41]Skin biopsy and histopathological examination with immunofluorescence shows atrophic changes in the epidermis with vacuolar degeneration, band-like infiltration of immunoglobulins, and complement along the basal membrane (positive direct immunofluorescence; absent in PLE).ANA, anti-Ro (SS-A), and anti-La (SS-B) tests should be obtained. In PLE they are negative.
Lymphocytic infiltration
Clinical signs include persistent plaques and papules, similar to PLE. [42] Signs persists longer than PLE.
Repetitive photoprovocation on previously non-UV-exposed predilection sites leads to the induction of typical skin lesions within a few days.Histopathological examination shows similar signs to PLE, but but with no sub-epidermal oedema.

Polymyalgia rheumatica

Giant cell arteritis (GCA) or temporal arteritis
New-onset unilateral headache, jaw claudication associated with chewing tough foods, diffuse mandibular discomfort, dental discomfort, sinus pain and pressure, and/or tongue pain are associated with GCA. Blindness, diplopia, or blurry vision and an abnormally thickened, tender, erythematous, or nodular temporal artery are also found. [8]
A positive temporal artery biopsy showing a granulomatous vasculitis confirms the diagnosis of GCA; however, results may be positive in PMR patients without GCA symptoms.
Late-onset rheumatoid arthritis (RA)
Presentation may be very similar to PMR; however, the absence of a prompt response to low-dose corticosteroids distinguishes the two. The peripheral musculoskeletal symptoms of late-onset RA do not respond rapidly. [5] Some with RA will respond to 10 to 20 mg of prednisolone.
Elevated rheumatoid factor and persistently raised plasma viscosity. [24] Positive anti-CCP antibody assays. [3] Anti-CCP assays were 61.4% sensitive and 100% specific for the diagnosis of late-onset RA. [25]Repeat x-ray of hands, delayed for months after the initial test, is performed to assess other affected joint damage. [5]
Hypothyroidism
May show similar signs of muscle and joint pain, weakness in the extremities, and fatigue; however, delayed relaxation of deep tendon reflexes (a rare finding) is strongly suggestive of hypothyroidism. [5]
An elevated TSH helps to differentiate hypothyroidism. [5] Creatine phosphokinase may also be elevated.
Fibromyalgia
Compared with PMR, fibromyalgia pain tends to be more widespread and is not associated with shoulder/hip girdle stiffness. The pain does not typically improve with 10 to 20 mg of daily prednisolone as is characteristic of PMR. [5] [26]
The ESR and CRP are normal [26]
Paraneoplastic syndrome
May present with constitutional symptoms and proximal muscle pain easily confused with the shoulder and hip girdle stiffness found in PMR. Paraneoplastic syndrome symptoms usually do not respond to low-dose corticosteroid treatment. A thorough tumour work-up should be reserved for those unresponsive to low-dose glucocorticoid therapy. Removal of the tumour leads to a resolution of symptoms. [1]The Lambert-Eaton syndrome, a paraneoplastic condition associated with small-cell lung cancer, may cause proximal weakness that improves later in the day, a feature similar to the symptoms of PMR.
Tumour screening includes routine baseline tests including a CXR, an FBC, a chemistry panel, and urinalysis. Age-appropriate cancer screening tests should also be performed (i.e., faecal occult blood testing, colonoscopy, mammogram). Additional specialised testing should be directed by the history, the examination findings, and any abnormalities found on the routine CXR and laboratory tests.
Polymyositis
Symmetrical weakness of shoulder and pelvic girdles. [5]
Elevated muscle enzyme levels (i.e., creatine phosphokinase) often with a positive anti-nuclear antibody titre. Characteristic changes in electromyography associated with polymyositis include increased needle insertional activity, spontaneous fibrillations, low-amplitude, short-duration polyphasic motor potentials, and complex repetitive discharges. Diagnosis is confirmed with muscle biopsy, indicating immune cell infiltration and destruction of muscle fibres. [5]
Overuse bursitis/tendonitis
No systemic symptoms as in PMR. Typically unilateral shoulder involvement without bilateral involvement. [5]
A normal ESR helps exclude PMR; however, about 20% of PMR patients have a normal result. [5]
Remitting seronegative symmetric synovitis with pitting oedema
Polyarthritis and bilateral oedema of both hands found typically in individuals older than 50 years. [27] [28]
MRI shows predominantly a tenosynovitis. [28] [5] Serum vascular endothelial growth factor may be useful in diagnosis and monitoring of disease activity, but this is not currently standard practice. [29]

Popliteal cyst

Deep vein thrombosis
Patients may have underlying risk factors for development of DVT.May present with acute calf pain and/or swelling without associated knee pathology.
Venous ultrasound will demonstrate thrombus inside the vein.
Popliteal haematoma
Patients may have a history of recent trauma or treatment with anticoagulants.
Ultrasound will demonstrate a haematoma in the affected area.CT and MRI can also identify the haematoma.
Popliteal muscle tear
May cause pain out of proportion localised at the site of the tear.
Ultrasound, MRI, and CT will demonstrate the muscle tear.
Knee effusion
May lead to excessive intra-articular fluid in areas other than the cyst location.
Ultrasound, MRI, and CT will demonstrate the knee effusion.
Popliteal aneurysm
May cause a pulsatile mass in the popliteal fossa.
Arterial ultrasound will demonstrate the aneurysm.
Popliteal vein aneurysm
May cause a soft compressible mass in the popliteal fossa.
Venous ultrasound will demonstrate popliteal vein aneurysm.
Popliteal soft tissue mass
May show a palpable firm mass.
Ultrasound, MRI, and CT will demonstrate the mass.
Popliteal lymphocele
Typically a firmer palpable mass than popliteal cyst.
Duplex ultrasound demonstrates cyst with clear fluid and acoustic enhancement posteriorly.
Popliteal abscess
May show a tender, fluctuant collection with erythema.There may be signs of infection such as fever.
Duplex ultrasound or CT scan will demonstrate non-cystic, heterogeneous collection.
Popliteal fossa varicosities
There may be visible varicosities in the popliteal fossa.
Venous duplex will demonstrate varicosities.

Porphyria cutanea tarda

Variegate porphyria (VP)
Blistering skin lesions are common and identical to PCT.
Differentiated most rapidly by the plasma fluorescence emission spectrum (maximum at ~626 nm). [6] [11] [12] Urinary porphyrins in VP are predominantly coproporphyrin III and faecal porphyrins coproporphyrin III and protoporphyrin. Urinary porphyrin precursors may be elevated.
Hereditary coproporphyria (HCP)
Blistering skin lesions identical to PCT, but less common than in VP.
Urinary and faecal porphyrins in HCP are predominantly coproporphyrin III. Urinary porphyrin precursors may be elevated.
Congenital erythropoietic porphyria
More severe blistering skin lesions in moderate to severe cases. Mild cases can resemble PCT.
Substantial elevation in erythrocyte porphyrins. Urinary porphyrins predominantly uroporphyrin I and coproporphyrin I and faecal porphyrins coproporphyrin I.
Pseudoporphyria
Blistering skin lesions over sun-exposed areas identical to those in PCT. A photosensitising drug can be identified in some cases.
Plasma porphyrin levels normal.
Hepatoerythropoietic porphyria
Usually begins in early childhood and resembles congenital erythropoietic porphyria.
Marked elevations of erythrocyte porphyrins as well as urinary and plasma uroporphyrin and heptacarboxyl porphyrin. Erythrocyte UROD activity <10% of normal. Homozygous or compound heterozygous UROD mutations.

Post-traumatic stress disorder

Depression
May occur after exposure to trauma, but predominant symptoms are low mood, lack of energy, loss of interest, and suicidal ideation.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Specific phobias
Fear and avoidance are cued by specific objects or situations.Re-experiencing and restricted range of affect are not features.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Panic disorder
Recurrent, unexpected panic attacks not cued by stimuli that recall a specific trauma (i.e., situationally bound or predisposed).
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Adjustment disorders
Variable presentation with symptoms of low mood, anxiety, worry, traumatic stress symptoms, and feelings of inability to cope, plan ahead, or carry on.Symptom intensity is usually less.Precipitating stressor may or may not meet Criterion A of DSM-IV-TR diagnostic criteria.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Dissociative disorders
Persistent and recurrent feelings of detachment and estrangement from oneself (depersonalisation disorder).Gaps in recall, often related to traumatic events (dissociative amnesia).Absence of re-experiencing and hyperarousal symptoms.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Obsessive-compulsive disorder
Recurrent intrusive thoughts, which are perceived as inappropriate, but are not related to a traumatic experience.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]
Psychosis
Flashbacks and vivid intrusive images that are accompanied by perceptual and cognitive disorganisation.
Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD Module): patient does not meet criteria for diagnosis of PTSD. [41]Clinician-Administered PTSD Scale: patient does not meet criteria for diagnosis of PTSD. [40]PTSD Symptom Scale-Interview Version: patient does not meet criteria for diagnosis of PTSD. [42]

Postnatal depression

Minor mood disorder (postnatal blues or 'baby blues')
Causes transient emotional lability during the first week after birth and has a wide variety of symptoms typical of low and high mood.Care of the baby is not impaired, hopelessness and worthlessness are not prominent, and women do not feel suicidal.Self-limiting, but assessment should ensure that the woman is not and does not become more severely depressed.
Clinical diagnosis.
Postnatal (puerperal) psychosis
Women with a history of bipolar disorder (1 in 4 deliveries) or a previous puerperal psychosis (1 in 2 deliveries) are at considerably higher risk.Acute onset of a manic or depressive psychosis soon after birth. There is a very close relationship to childbirth, with >90% of women experiencing an onset in the first postnatal week and 73% of women experiencing an onset of symptoms by day 3. [55] [56]
Clinical diagnosis.
Bipolar disorder
Suspicious features include atypical features (DSM-IV criteria), [2] racing thoughts, and psychotic symptoms.Should be screened for in all patients presenting with suspected postnatal depression.A family history of bipolar disorder may be present.The Mood Disorder Questionnaire [50] [57] is the most useful test available for screening for bipolar disorder. However, it has not been definitively validated.Once the risk is recognised, it is necessary to follow up with a more comprehensive psychiatric assessment. [57]
Clinical diagnosis.
Thyroid dysfunction
Possible symptoms of hyperthyroidism (e.g., weight loss, sweating, nervousness, palpitations) or hypothyroidism (e.g., sluggishness, constipation, cold intolerance).The time frame for postnatal (painless/lymphocytic) thyroiditis, which is characterised by transient hyper- and hypothyroid phases, may overlap with that for postnatal depression,although there is no established causal relationship between the 2 conditions. [54]
TSH low (hyperthyroidism) or high (primary hypothyroidism).
Anaemia
Symptoms and signs include pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise.Clinical features specific to the underlying cause may also be identified.
Hb <12 g/dL in females or <14 g/dL in males.Urine drug screen may be positive in substance abuse and identifies the substance taken.
Organic brain dysfunction
Patients have clinical symptoms or signs of the underlying cause. Brain dysfunction may be due to primary cerebral or systemic disease.
Brain CT or MRI may identify a structural neurological abnormality.Other investigations are targeted to the suspected underlying cause.
Exogenous toxic substances or hormones
History of therapeutic use and/or abuse of known causative substances or hormones.Other symptoms and signs specific to the substance or substances involved may be present.
Urine drug screen may be positive in substance abuse and identifies the substance taken. However, drug screens are not definitive for drug misuse.
Postnatal symptoms unrelated to depression
Symptoms such as sleep disturbance, weight change, and loss of energy commonly occur following childbirth without any associated depression.Characteristic mood changes of depression are absent.
Clinical diagnosis.

Pre-eclampsia

Chronic hypertension
Pre-existing hypertension prior to pregnancy.Retinopathy commonly seen in longstanding disease.
Urinalysis: absence of new-onset proteinuria.
Gestational hypertension
No differentiating signs or symptoms.
Urinalysis: absence of proteinuria.
Epilepsy
History of epilepsy or seizures before pregnancy.BP normal.Focal neurological deficits or symptoms.
Urinalysis: absence of proteinuria.
Antiphospholipid antibody syndrome
History of repeated early pregnancy loss.History of venous thrombosis, stroke, or TIA.
Lupus anticoagulant: positive.Anticardiolipin antibodies: medium or high titre.Anti-beta-2-glycoprotein I: titre >99th percentile.
Thrombotic thrombocytopenic purpura
Presentation before 20 weeks' gestation.Thrombosis, purpura, or spontaneous bleeding.Fever.Neurological signs (e.g., seizures) in the absence of signs of severe pre-eclampsia.
ADAMTS-13 activity assay and inhibitor titres: decreased activity.
Haemolytic uraemic syndrome
Presentation before 20 weeks' gestation.Microangiopathic haemolytic anaemia in the absence of signs of severe pre-eclampsia.Thrombosis.Renal failure in the absence of signs of severe pre-eclampsia.Diarrhoea (especially bloody diarrhoea), nausea, or vomiting.
Peripheral blood smear: presence of schistocytes.FBC: anaemia, thrombocytopenia.
Renal disease
History of renal disease before pregnancy.
Serum creatinine: elevated in the absence of signs of severe pre-eclampsia.
Liver disease
History of liver disease before pregnancy.History of alcohol abuse.Jaundice.BP is normal.Hepatomegaly.
Urinalysis: absence of proteinuria.Serum bilirubin: elevated.LFTs: very high in cases of viral disease.Blood glucose: decreased in cases of acute fatty liver of pregnancy.
Gallbladder disease
History of biliary pain before pregnancy.RUQ pain is colicky in nature, and is usually intense, lasting >30 minutes.BP is normal.Distended, tender gallbladder may be palpable.
LFTs: elevated alkaline phosphatase, gamma-GT, and bilirubin.RUQ ultrasound: pericholecystic fluid; distended gallbladder; thickened gallbladder wall; gallstones; positive Murphy sign.
Pancreatic disease
History prior to pregnancy.History of alcohol abuse.BP is normal.Steatorrhoea.Jaundice.Nausea and vomiting.
Abdominal ultrasound: structural/anatomical changes including cavities; duct irregularity; contour irregularity of head/body; calcification.Abdominal CT scan: pancreatic calcifications; focal or diffuse enlargement of the pancreas; ductal dilation; vascular complications.Abdominal x-ray: pancreatic calcifications.Serum amylase: elevated.

Precocious puberty

Premature thelarche
Isolated, often fluctuating, unilateral or bilateral breast development.Unaccompanied by other signs of puberty.Growth velocity is normal and bone age is not advanced.Presents typically between 6 months and 4 years of age in girls.Benign and self-limiting.
Clinical diagnosis.Typically associated with only a minimal degree or no increase of FSH secretion; LH is normal.US pelvis may demonstrate small follicular development.
Premature adrenarche
Early or exaggerated adrenarche.Pubic hair development. No breast development and only a minimal increase in growth velocity.Typically presents between 7 and 9 years, particularly in girls, and those in the black population.Congenital adrenal hyperplasia and virilising adrenal tumours need to be excluded.
Clinical diagnosis.Mild increase in serum androgens: testosterone and dehydroepiandrostenedione sulphate (DHEAS).GnRH test is normal with prepubertal concentrations of FSH and LH.
Congenital adrenal hyperplasia (CAH)
The classic form, 21-hydroxylase, presents as ambiguous genitalia in girls and precocious puberty in boys. In addition, the salt wasting form may present with an adrenal crisis.An increased height velocity, advanced bone age, and genital maturation in the absence of testicular enlargement in boys or breast development in girls (i.e., disconsonant puberty) suggests CAH.
Serum 17-hydroxyprogesterone (17-OHP) is elevated in 21-hydroxylase classic CAH.Other adrenal hormone precursors are elevated in other forms of CAH.A standard ACTH stimulation test is often necessary to stimulate these adrenal hormone precursors.
Adrenal tumours
A short history of virilisation, accelerated growth rate, and advanced bone age is present. Cushing's syndrome may be present if there is hypersecretion of cortisol.
Urinary steroid profile analysis reveals an abnormal pattern of adrenal hormone secretion.Imaging of the adrenal glands identifies the tumour.
Cushing's syndrome
Due to adrenal disease.Presents with virilisation, without testicular enlargement in boys or breast development in girls, in addition to typical Cushingoid features such as central obesity with thin extremities, nuchal fat pad, moon facies, purple striae, bruisability.
Twenty-four-hour urinary free cortisol is elevated.8 a.m. serum cortisol is elevated with loss of diurnal rhythm.ACTH is undetectable.Low and high dexamethasone suppression tests show failure of cortisol suppression.
Polycystic ovary syndrome
Females present with obesity, hirsutism, acne, oily skin, and weight gain.Virilisation (pubic and axillary hair) may be present without breast development.On examination the patient is usually obese and may have acanthosis nigricans.
US pelvis may show polycystic ovaries with a peripheral pattern of follicular distribution, and variable endometrial thickness.Serum testosterone, androstenedione, DHEAS, and basal LH are elevated.Fasting insulin is elevated, with concomitant lowering of sex hormone binding globulin, indicating insulin resistance.
Primary hypothyroidism
Long-standing hypothyroidism can result in high TSH with elevated FSH, leading to isolated breast development or testicular enlargement without other secondary sexual characteristics.There is no pubertal progression in the majority of cases; bone age is delayed and growth velocity is poor.TSH directly activates the FSH receptor, as the two hormones have structural similarity.
Low FT4; elevated TSH.

Premature labour

Placental abruption
This can occur with or without vaginal bleeding (concealed abruption). Signs of fetal distress (abnormal fetal heart rate pattern) or the presence of blood in the vagina increase its likelihood. It may also lead to preterm labour.
A non-stress test may reveal an abnormal fetal heart rate pattern.Kleihauer's test: this blood test demonstrates fetal cells in the maternal circulation.
Urinary tract infection (UTI)
A previous history of UTI, abdominal pain, dysuria, or increased frequency of urination. This may lead to preterm labour.
Urinalysis for nitrites, leukocytes, and protein.Urine culture: positive growth of specific micro-organism.
Ovarian cyst
Can mimic preterm labour. May have non-specific signs of abdominal pain or backache. May present with tachycardia, low BP, nausea and vomiting, or localised abdominal pain.
Ultrasound (US) pelvis: may reveal an ovarian mass or free fluid in the abdomen.
Ovarian torsion
Can mimic preterm labour. May present with non-specific abdominal or back pain and associated symptoms of nausea and vomiting.
US pelvis: may reveal an ovarian mass or free fluid in the abdomen.CT abdomen: generally avoided in pregnancy but will demonstrate ovarian torsion.
Appendicitis
Abdominal pain may be higher in the abdomen and more diffuse. May have accompanying symptoms of nausea, vomiting, and loss of appetite.
US abdomen: may reveal an appendix mass.WBC and CRP may be elevated.

Premature newborn care

Small for gestational age (SGA)
SGA describes an infant who is below the 10th percentile for weight, length, or head circumference.Some SGA infants are constitutionally small without intrauterine growth restriction (IUGR) but others are associated with IUGR.Although an SGA infant may have a low birth weight, the infant is not necessarily premature and, if not, does not manifest disease or physical findings commonly associated with prematurity.
Physical assessment and the revised Ballard score aid in the diagnosis.
Intrauterine growth restriction (IUGR)
IUGR is a failure to reach the full growth potential and is a risk factor for preterm delivery.The IUGR infant must be examined carefully to identify potential causes for growth retardation in addition to recognition of manifestations related to prematurity. IUGR babies may be symmetrical or asymmetrical (with head-sparing).
Physical assessment and the revised Ballard score aid in the diagnosis.Symmetrical IUGR is associated with chromosomal anomalies such as trisomy 21, 18 and 13, and with fetal alcohol and intrauterine infections such as cytomegalovirus or other congenital infections.Asymmetrical IUGR where the head growth is spared is evident in the last trimester and is associated with maternal hypertension, malnutrition or other maternal debilitating conditions.

Premature ovarian failure

Pregnancy
History of unprotected intercourse.
Serum or urine hCG: positive.
Polycystic ovary syndrome
Slowly progressive symptoms, obesity, hirsutism, acne, deepening of voice, male pattern hair growth or loss, oily skin, weight gain, oligoanovulatory cycles to amenorrhoea (if peripubertal onset, may present with delayed menarche), history of premature pubarche, androgenic alopecia, acanthosis nigricans, increased waist-hip ratio, and clitoromegaly.
Serum hCG: negative; serum FSH: normal; serum oestradiol: normal to elevated; serum AMH: elevated; serum TSH: normal; serum prolactin: normal; serum dehydroepiandrosterone sulfate (DHEAS): elevated; total serum testosterone: elevated, marked elevation suggests ovarian/adrenal tumour; pelvic ultrasound: polycystic ovaries, variable endometrial stripe.
Anorexia nervosa
Low BMI (10% less than ideal body weight), normal secondary sexual characteristics, normal external and internal genitalia.
Serum hCG: negative; serum FSH: low to normal (FSH assays have wide ranges, depending not only on cycle time but also on patient age); serum oestradiol: low; serum AMH: low to normal; serum TSH: normal; serum prolactin: normal; pelvic ultrasound: thin endometrial stripe.
Strenuous exercise
Weight loss, anorexia, sleep disturbances, dry skin, prescription drugs, normal secondary sexual characteristics, and normal external and internal genitalia.
Low BMI (10% less than ideal body weight); serum hCG: negative; serum FSH: low to normal (FSH assays have wide ranges, depending not only on cycle time but also on patient age); serum oestradiol: low; serum TSH: normal; serum prolactin: normal; pelvic ultrasound: thin endometrial stripe.
Emotional or physical stress
Weight loss, anorexia, sleep disturbances, dry skin, prescription drugs, normal secondary sexual characteristics, and normal external and internal genitalia.
Low BMI (10% less than ideal body weight); serum hCG: negative; serum FSH: low to normal (FSH assays have wide ranges, depending not only on cycle time but also on patient age); serum oestradiol: low; serum TSH: normal; serum prolactin: normal; pelvic ultrasound: thin endometrial stripe.
Sheehan's syndrome
Severe obstetric haemorrhage, hypotension, and shock with postpartum panhypopituitarism (after volume and blood resuscitation), nausea, vomiting, lethargy, failure to breastfeed, slowed mental function, fatigue, weight loss, delayed symptoms of hypothyroidism, postural hypotension, loss of axillary and pubic hair, adrenal crisis (with skin depigmentation), rapidly involuting breasts, and periorbital oedema.
Serum hCG: negative; serum FSH: low; serum oestradiol: low; serum TSH: low; serum T4: low; serum prolactin: low; serum growth hormone: low; serum ACTH: low to normal; serum sodium: may be low; serum cortisol (morning): may be low; MRI brain: sella empty or filled with CSF, pituitary gland may be small; pelvic ultrasound: thin to variable endometrial stripe.
Androgen-producing ovarian tumour
Rapidly progressive symptoms, obesity, hirsutism, acne, deepening voice, male pattern hair growth or loss, oily skin, weight gain, oligoanovulatory cycles to amenorrhoea; androgenic alopecia, clitoromegaly, male pattern hair growth, increased muscle mass.
MRI abdomen and pelvis would show an ovarian mass; free serum testosterone: elevated; total serum testosterone: elevated (<200 nanograms/dL [<6.94 nanomol/L]); serum DHEAS: normal; serum FSH, LH, TSH, and prolactin: normal; serum oestradiol: normal to elevated.
Hyperprolactinaemia
Galactorrhoea (some patients), headache or visual disturbances (prolactinoma); may present with oligomenorrhoea if prolactin levels are not extremely elevated; visual field deficit (some patients).
MRI brain may show pituitary tumour; serum prolactin: elevated; >100 nanograms/mL is highly suggestive of prolactinoma; serum FSH and LH: low to normal; serum oestradiol: low.
Medication-induced amenorrhoea
Antipsychotic medications are known to increase the risk of hyperprolactinaemia and menstrual irregularities due to lessened inhibition by dopamine.
Clinical diagnosis.
Congenital adrenal hyperplasia (non-classic)
Presents in late childhood to early adult life; obesity, hirsutism, acne, weight gain, history of premature pubarche; androgenic alopecia.
Serum 17-hydroxyprogesterone (17-OHP) fasting levels >200 nanograms/dL (>6.06 nanomol/L); total serum testosterone: elevated; free serum testosterone: elevated; serum DHEAS: elevated; serum FSH, LH, TSH, and prolactin: normal; serum oestradiol: normal to elevated.
Primary amenorrhoea
Lack of menses by age 15 years in a patient with appropriate development of secondary sexual characteristics, or absent menses by age 13 years and no other pubertal maturation.
Assessment begins with clinical features (assessment of breast development and hair patterns), FSH testing, and presence or absence of normal female reproductive tract on ultrasound. At times, a karyotype and/or serum testosterone measurements may be helpful.
Turner's syndrome
Physical features include short stature, webbed neck, cubitus valgus (increased carrying angle of arms), and lack of sexual development at puberty.
Karyotype of Turner's syndrome is 45,XO.
Asherman's syndrome
Amenorrhoea or light, but regular, periods.No signs of hypo-oestrogenism.History of endometrial curettage or severe post-partum haemorrhage.
Transvaginal ultrasound, saline sono-contrast sonography, or hysteroscopy shows scar formation.
Hypothyroidism
Frequently insidious onset of fatigue, goitre, exophthalmos, lid lag, bradycardia, or skin changes.
Low free T4, elevated TSH.

Premenstrual syndrome and dysphoric disorder

Depression
Patient meets DSM-IV criteria for major depression. Depression symptoms include low mood, low energy, anhedonia, appetite change, sleep disturbance, difficulty in concentrating, and thoughts of suicide.Depression may co-exist with PMS or PMDD in up to 50% of cases. A diagnosis of PMS or PMDD may predate a diagnosis of depression. [16] Major depression and PMDD may co-exist. Criteria are different but not exclusive.
Diagnosis is clinical.
Thyroid disease
Hypothyroid symptoms and signs include weight gain, constipation, cold intolerance, depression, dry skin, and delayed deep tendon reflexes.Hyperthyroid signs and symptoms include weight loss, poor sleep, heat intolerance, heart rhythm disturbance such as atrial fibrillation, and hyper-reflexia.
Thyroid blood tests may show abnormalities reflecting an overactive or underactive thyroid.
Generalised anxiety disorder
Patient meets DSM-IV criteria for generalised anxiety disorder. Symptoms of anxiety include palpitations and feelings of fear. Triggers may be identified for anxiety attacks, and patient shows avoidance of these triggers.Chronic or situational anxiety does not vary with the menstrual cycle.Generalised anxiety disorder and PMDD may co-exist. Criteria are different but not exclusive.
Diagnosis is clinical.
Mastalgia
Symptoms may be limited to breast tenderness and swelling, in which case mastalgia should be considered.Mastalgia may be present other than during the luteal phase but worsens during the luteal phase.
Diagnosis is clinical.

Pressure ulcer

Venous ulcers
Commonly occur on lower legs near ankles, frequently accompanied by skin staining.May be painful.May be associated with lipodermatosclerosis, in which the lower part of the leg is hardened.
Clinical picture supported by vascular assessment to demonstrate venous insufficiency.
Arterial ulcers
Found on feet, heels, or toes.Surrounding skin often white and shiny.Typically most painful in bed; pain sometimes relieved by having the legs dependent.Ulcers often have a pale base and a punched-out appearance.
Vascular assessment and an ankle brachial index <0.7.
Diabetic neuropathy
Neuropathic diabetic ulcers are caused by pressure resulting often from ill-fitting shoes or failure to reposition limb due to impaired perception of pain. Ulcers commonly occur on the toes, heel, or other parts of the foot.
HbA1c may support poor glucose control.
Pyoderma gangrenosum
Most often affects people in their 40s or 50s.In approximately 50% of patients, it is associated with other conditions, including inflammatory bowel disease.Characteristically, the edge of an ulcer is purple and undermined (tunnelled) as it enlarges.Ulcers are painful and most commonly occur on the legs. Unlike pressure ulcers, pyoderma gangrenosum ulcers start as a small discrete area and enlarge rapidly.
There are no differentiating tests; diagnosis is clinical.
Osteomyelitis
Typical symptoms are bone pain, tenderness, and swelling. May be a previous history of osteomyelitis, recent surgery, or penetrating injury. If bone is exposed in a suspected pressure ulcer, osteomyelitis should be excluded. [24]
MRI is diagnostic.Inflammatory markers are elevated.

Priapism

Peyronie's disease
Penis shows variable degree of curvature on erection. Palpation may detect a fibrotic plaque on shaft of penis.
Ultrasound may show calcifications within penile plaque.
Penile implant
The permanent erection that may accompany some penile implants may mimic priapism (pseudopriapism). Clinical history is usually sufficient to make the diagnosis.
There are no distinguishing tests.

Primary aldosteronism

Essential HTN
No differentiating signs or symptoms.
Aldosterone/renin ratio will be normal if performed off interfering medicines. May be elevated if patient receiving medicines (such as beta-blockers) that cause false positives, in which case test should be repeated after such medicines are withdrawn for at least 2 (and preferably 4) weeks.A normal ratio in a patient receiving medications that can cause false positives makes PA highly unlikely.In a minority of cases of PA, there is unprovoked hypokalaemia.
Thiazide-induced hypokalaemia in patient with essential HTN
History of use of thiazides.
Aldosterone/renin ratio will be normal after correcting hypokalaemia and withdrawing thiazide for at least 6 weeks. [59]
Secondary HTN
Known renal artery stenosis, history of arterial disease elsewhere, or risk factors for atherosclerosis (e.g., smoking, diabetes, and hyperlipidaemia).
Aldosterone/renin ratio will be normal or low. [58] [59]Imaging studies will demonstrate renal artery stenosis or reninoma.
Liddle's syndrome
Family history of Liddle's syndrome.Usually presents in childhood.
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the ratio usually is normal. [82] [59]
Syndrome of apparent mineralocorticoid excess
Family history of this syndrome. Hereditary form usually presents in childhood.History of excessive consumption of liquorice, which can lead to an acquired form.
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the ratio usually is normal. Urinary free cortisol/cortisone ratio is elevated. [82] [59]
Hypertensive forms of congenital adrenal hyperplasia
Family history of congenital adrenal hyperplasia due to 11beta-hydroxylase or 17alpha-hydroxylase deficiency.Usually presents in childhood.History of either virilisation (in the case of 11beta-hydroxylase deficiency) or feminisation (in the case of 17alpha-hydroxylase deficiency).
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.In 11beta-hydroxylase deficiency, plasma cortisol and corticosterone are low, whereas basal or ACTH-stimulated levels of deoxycorticosterone and 11-deoxycortisol are elevated.In 17alpha-hydroxylase deficiency, plasma levels of 17alpha-hydroxyprogesterone, 11-deoxycortisol, and cortisol are reduced, whereas gonadotrophins (LH and FSH) are increased. [82] [59]
Primary glucocorticoid resistance
Family history of this syndrome (but can be acquired).May be associated with androgenisation.
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.Associated with increased ACTH and cortisol levels, and resistance of cortisol to adrenal suppression by dexamethasone, in the absence of clinical stigmata of Cushing's syndrome. [82] [59]
Ectopic ACTH syndrome
Clinical findings of underlying tumour.
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.Evidence of underlying tumour on imaging studies.Cortisol and ACTH levels elevated and non-suppressible with high-dose dexamethasone. [82] [59]
Activating mutations of the mineralocorticoid receptor
Family history of this syndrome.Exacerbation of HTN and development of hypokalaemia during pregnancy.
Although patients are usually hypokalaemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal. [82] [59]
Pseudohypoaldosteronism type II
Family history of this syndrome.
Although renin levels are usually suppressed and aldosterone/renin ratio is often elevated, plasma potassium levels are elevated. [82] [59]

Primary biliary cirrhosis

Obstructive bile duct lesion
Previous history of bile duct surgery/obstruction possible.Pain much more prominent than with primary biliary cirrhosis (PBC).Bacterial cholangitis as a complication much more likely than in PBC.
Antimitochondrial antibody (AMA) or disease-specific ANA not associated.Abdominal ultrasound finding of duct dilatation (confirmed by magnetic resonance cholangiopancreatography [MRCP] or ERCP according to local practice) confirmatory.
Primary sclerosing cholangitis
Different demographics than PBC (primary sclerosing cholangitis [PSC] is more common in younger males).Association with inflammatory bowel disease.
AMA or disease-specific ANA not associated.Perinuclear antineutrophil cytoplasmic antibody suggestive of PSC may be present. This marker is absent in a majority of PSC patients.Abdominal ultrasound finding of duct irregularity (confirmed by MRCP or ERCP according to local practice) is confirmatory.Liver biopsy characteristic of PSC.
Drug-induced cholestasis
History of relevant drug exposure. [31] Can also occur as a consequence of exposure to herbal/non-pharmaceutical preparations.
AMA or disease-specific ANA not associated.Liver biopsy characteristic of cholestasis.
Cholestasis of pregnancy
Associated with pregnancy. [32]
AMA or disease-specific ANA not associated.Bile salts elevated, transaminases more prominent than alkaline phosphatases.
Infiltrative malignancy within liver
Associated with other systemic features suggestive of malignant disease.
Cross-sectional imaging.Liver biopsy if doubt persists.

Primary hyperparathyroidism

Familial hypocalciuric hypercalaemia (FHH)
Patients with FHH appear healthy. There may be a positive family history of other members with high serum calcium without objective symptoms of nephrolithiasis or bone disease.
Renal calcium to creatinine clearance ratio is lower compared with patients with PHPT. SI units should be used instead of or in addition to those currently adopted.Diagnosis can be confirmed with genetic testing.
Humoral hypercalcaemia of malignancy
Positive history of solid tumour malignancy. Other manifestations of systemic signs of illness such as weight loss, fatigue, pain, and feelings of ill health.Humoral hypercalcaemia of malignancy occurs in patients with solid tumours of the lung, breast, kidney, ovary, and head and neck; there is typically no bone metastasis. This process is mediated primarily by PTH-related-protein/peptide (PTHrP). PTHrP also plays a role in the hypercalcaemia associated with bone metastases and multiple myeloma.
Intact serum PTH is appropriately low, but PTHrP would be elevated if the source is from an ectopic malignancy.Mild hypokalaemic hypochloraemic alkalosis may be present.CXR, mammogram, and urinary analysis should be used to evaluate for malignancies.
Multiple myeloma
Multiple myeloma may show weight loss.
Bone x-ray shows lytic bone lesions, characteristic of multiple myeloma.Gamma globulin assessment defines the disorder as well.Serum creatinine and urea levels with serum protein electrophoresis rules out multiple myeloma.
Milk-alkali syndrome
A history of excessive intake of antacids.
Calcium levels are high, but intact serum PTH is low.
Sarcoidosis
Sarcoidosis occurs with a dry cough.
CXR shows thoracic lymphadenopathy and parenchymal lung disease.Angiotensin-converting enzyme levels may be elevated.Patients may also show eosinophilia or elevated ESR.Calcium is high, but intact serum PTH is low.
Parathyroid carcinoma
Twenty percent to 50% of patients with parathyroid carcinoma have a palpable mass in the neck. Patients may also have hoarseness.
May have significantly elevated calcium (>3.25 mmol/L [>13.0 mg/dL] is suggestive), which should prompt suspicion. Calcium is usually higher than in patients with sporadic, benign disease.
Hypervitaminosis D
History of excessive vitamin D intake.
25-Hydroxyvitamin D level >100 nanograms/mL indicates hypervitaminosis D.Calcium is high, but intact serum PTH is low.
Thyrotoxicosis
Tachycardia, weight loss, nervousness, and anxiousness are present in thyrotoxicosis.
TSH is low.Calcium is high, but intact serum PTH is low.
Chronic or acute leukaemia
Infections, fever, weight loss, lymphadenopathy, and abnormal bleeding are present in acute or chronic leukaemia.
FBC may show anaemia (low haemoglobin), too many leukocytes (leukocytosis), or too few leukocytes (leukopenia).Calcium is high, as well as PTH-related-protein/peptide.
Immobilisation
Patients have a history of being bed-bound or hospitalised for long periods of time, but may be without hyperparathyroid symptoms of nephrolithiasis, memory loss, and muscle cramps.
Serum calcium levels are often high with a low intact serum PTH level.
Thiazide diuretic therapy
Patients have a history of HTN and are on thiazide diuretic therapy.
Serum calcium levels should decrease when thiazide medicine is discontinued and intact serum PTH levels are low.Decreases in calcium excretion lead to hypercalcaemia, but without concomitant suppression of PTH. [37]

Primary hypothyroidism

Depression
Many of the symptoms of hypothyroidism, which are non-specific, can be caused by depressive disorders. Both disorders are common in primary care practice. [2] [5] The symptoms of hypothyroidism respond to thyroid hormone replacement therapy. Depressive disorders generally respond to treatment with antidepressants and/or behavioural therapy.
Hypothyroidism is diagnosed by an elevated TSH, which is normal in depression.
Alzheimer's dementia
In older patients the 2 conditions may be indistinguishable. [2] [5] Cognitive dysfunction in hypothyroidism responds to thyroid replacement therapy.
Patients with Alzheimer's dementia have normal TSH. CT of the head may show signs of atrophy.
Anaemia
Hypothyroidal and anaemic patients often have fatigue and dyspnoea on exertion. Primary hypothyroidism is associated with pernicious anaemia. [5] [13]
TSH is elevated in primary hypothyroidism and the anaemia is usually normocytic. In other forms of anaemia, the TSH is not elevated and the red cells indices are variable (e.g., macrocytosis in pernicious anaemia, microcytosis in iron deficiency anaemia).

Primary invasive breast cancer

Fibrocystic changes
Unlike breast cancer, fibrocystic changes are typically symmetrical and are associated with cyclical breast pain, which worsens in the luteal phase of menses. [70]Unlike the incidence of breast cancer, which increases with age, fibrocystic disease usually resolves at menopause.
Ultrasound scan can differentiate cysts from solid lesions.If necessary, biopsy of the involved area will confirm the diagnosis.
Fibroadenoma
Like fibrocystic changes, fibroadenomas tend to worsen during periods of elevated oestrogen levels (such as pregnancy) and decline in size during menopause.Palpation of a fibroadenoma reveals a smooth, well-demarcated and mobile mass. [71]
Ultrasound scans may be able to distinguish between a fibroadenoma (defined, oval contour) and a breast carcinoma (which may have ill-defined margins).Excision biopsy reveals fibroadenomas as well-delineated bosselated tumours, easily separated from surrounding breast tissue, and with a shiny and bulging surface on section.Histological analysis shows regular epithelial cells lining the duct-like structures, mixed with pale stroma.
Mastitis
Mastitis tends to affect a specific population: lactating women or women who have had a recent breast surgery.Examination finds an erythaematous, tender, and swollen breast.Unlike inflammatory breast cancer, mastitis is also associated with systemic signs and symptoms of infection, such as high fevers, chills, and influenza-like symptoms.Treatment of the underlying infection leads to resolution of these signs and symptoms.
Imaging studies demonstrate no underlying mass.The clinical presentation and response to antimicrobial agents will usually sufficiently differentiate these conditions.Skin biopsy (if needed) will show no evidence of tumour cells within the dermal lymphatics.

Primary sclerosing cholangitis

Secondary sclerosing cholangitis
History significant for a potential cause of the pathological process (e.g., intraductal stone disease, recurrent pyogenic cholangitis, recurrent pancreatitis, surgical trauma to the bile duct, bile duct ischaemia, caustic injury from intra-arterial chemotherapy, malignancy). [21]No differentiating signs/symptoms.
Investigations are targeted at the underlying cause. Identification of an underlying cause excludes primary sclerosing cholangitis.
Immunoglobulin G4 cholangitis
Predominantly affects elderly males (average age 65). [46]Obstructive jaundice is a more frequent presentation.Not associated with inflammatory bowel disease.
Elevated serum IgG4. [47]Cholangiography more frequently demonstrates stricture of the distal common bile duct and irregular narrowing of the main pancreatic duct.May be associated autoimmune pancreatitis (elevated amylase and lipase, diffuse or localised enlargement of the pancreas on imaging).IgG4 plasma cell infiltration in liver or duodenal tissue.Dramatic response to corticosteroids.
Autoimmune hepatitis
Female predominance.
Higher titres of antinuclear antibodies (ANA) and/or smooth muscle antibodies. [48] [49]Elevated levels of serum immunoglobulin G (IgG).More marked aminotransferase elevations and less prominent alkaline phosphatase elevations.Normal cholangiogram.Liver biopsy with interface hepatitis, plasma cell infiltrate, bridging necrosis.Biochemical improvement with corticosteroid treatment in most cases.Diagnostic criteria published by the International Autoimmune Hepatitis Group. [49]
Primary biliary cirrhosis
Predominantly affects middle-aged women.Not associated with inflammatory bowel disease.
Antimitochondrial antibody present in 95% of cases. [50]Elevated levels of serum immunoglobulin M (IgM).Normal cholangiogram (although decreased branching and narrowing of the intrahepatic ducts can be seen in patients with cirrhosis of any cause, and can be difficult to distinguish from intrahepatic PSC). [40]

Prion disease

Alzheimer's dementia (AD)
Generally a more chronic and rarely rapidly progressing dementia, but atypical cases can be mistaken for Creutzfeldt-Jakob disease (CJD). [83]CJD patients commonly present after 60 years of age, with deficits in memory and cognition in the absence of other disorders.Clinical features of CJD that are not commonly seen in AD include subacute onset and/or difficulty in co-ordination early on in the course. [84]
AD is a clinical diagnosis. The clinical history, performance on neuropsychological testing, and pattern of brain MRI atrophy, single photon emission computed tomography (SPECT) hypoperfusion, or PET scan hypometabolism may support the diagnosis of AD. An MRI that is diagnostic for CJD may rule out AD. View imageView imageView imagePET scanning with Pittsburgh compound B (may soon be a diagnostic test for AD. [85]
Lewy body dementia
In a research study with a large cohort, dementia with Lewy bodies was found to be the second most commonly mistaken dementia for Creutzfeldt-Jakob disease (CJD). [72] [86]Like CJD, dementia with Lewy bodies is a neurodegenerative disease that can present with cognitive impairment, visual hallucinations or disturbances, and parkinsonism. [87] [88]
This condition is best distinguished from CJD by diffusion-weighted imaging (DWI), attenuated diffusion coefficient map (ADC), or fluid-attenuated inversion recovery (FLAIR) imaging on brain MRI.View imageView imageView imageSPECT or PET scan may also reveal low dopamine transporter uptake in the basal ganglia. [88]Periodic sharp wave complexes are rarely seen on EEG in the late stages of Lewy body dementia.
Frontotemporal dementia
Although frontotemporal dementia (FTD) typically has a faster course than most memory and ageing disorders, it is seldom as rapidly progressive as CJD.Patients usually present with a frontal syndrome, including behavioural, personality, and cognitive changes, before the onset of dementia. [89] [90] [91]Unlike Creutzfeldt-Jakob disease (CJD), criteria for frontotemporal dementia exclude myoclonus and cerebellar ataxia. [92]
FTD is a clinical diagnosis. The clinical history, neurological examination, performance on neuropsychological testing, and pattern of brain MRI atrophy, SPECT hypoperfusion, or PET scan hypometabolism may support a diagnosis of FTD.An MRI (DWI and ADC sequences) that is diagnostic for CJD essentially rules out FTD.
Cortical basal syndrome (CBS)
Another progressive dementia that typically has a slower course than Creutzfeldt-Jakob disease (CJD).Visual, sensory, and motor deficits of cortical basal degeneration may initially suggest CJD. [60] [93]CBS is typically due to an underlying pathology of cortical basal degeneration or AD, and rarely CJD.
CBS is a clinical diagnosis, usually with an underlying pathological diagnosis of CBD or AD. The clinical history, neurological examination, performance on neuropsychological testing, and pattern of brain MRI atrophy, SPECT hypoperfusion, or PET scan hypometabolism may support a diagnosis of CBS.An MRI that is diagnostic for CJD rules out CBS.
Vasculitis
Vasculitides can cause dementia or encephalopathy when they affect the CNS. These disorders can be distinguished from Creutzfeldt-Jakob disease (CJD) by the presence of systemic or peripheral nervous system signs such as fever, weight loss, neuropathy, and organ involvement.Criteria used in the diagnosis of such disorders have been established by the American College of Rheumatology. [60] [94] [95] [96]
ESR and CRP are elevated.RF and ANA are positive.Perinuclear antineutrophilic cytoplasmic antibody (P-ANCA) and cytoplasmic antineutrophilic cytoplasmic antibody (C-ANCA) are positive.Brain angiogram demonstrates an intermittent narrowing 'sausage' appearance not seen in CJD.CSF may show evidence of inflammation, such as pleocytosis.Meningeal and brain biopsy shows inflammation of the blood vessels with lymphocytic infiltrate that is not present in CJD.Although serological rheumatological evaluation should be performed for elevated auto-antibodies, in isolated CNS vasculitis, these blood tests may be negative and systemic signs may be absent. [97]
Paraneoplastic limbic encephalitis and non-paraneoplastic autoimmune limbic encephalitis
Autoimmune disorders that mimic prion diseases include paraneoplastic limbic encephalitis and non-paraneoplastic autoimmune limbic encephalitis. [98]Paraneoplastic limbic encephalopathies typically occur in 2 forms: antibody-mediated autoimmune conditions or non-antibody autoimmune-mediated causes such as systemic (but non-CNS) cancers.Paraneoplastic disorders may present in patients with known or FHx of cancer, or even precede the detection of cancer entirely.If a paraneoplastic condition is suspected, body CT imaging with contrast is indicated. [60] [99] [100] [101]About 30% of these patients also present with seizures. [98] [99] [100]
Serum and CSF should be tested for elevated tumour markers and the presence of paraneoplastic antibodies.ESR and CRP are elevated.RF and ANA are positive.P-ANCA and C-ANCA are positive.Tumour markers such as CEA, CA-125, or PSA may be elevated.Paraneoplastic antibodies present: anti-Hu (ANNA-1), anti-Ta (anti-Ma2), anti-CV2 (anti-CRMP-5), anti-amphiphysin, anti-Yo (PCA-1), anti-nCMAg, anti-Ma1, anti-Ri (ANNA-2), anti-AMPAR, anti-N-methyl-D-aspartate receptor (NMDAR), anti-voltage-gated potassium channel (VGKC)-associated antibodies.
Limbic encephalopathy autoimmune antibody-mediated causes not related to cancers
Limbic encephalopathy can also be due to autoimmune antibody-mediated causes not associated with cancers, as seen in anti-VGKC antibodies and other antineutrophil antibodies, and Hashimoto's encephalopathy.Sometimes these antibodies are associated with cancers (paraneoplastic) and sometimes they are not (non-paraneoplastic). [98] [101] [102]
VGKC and anti-glutamic acid decarboxylase (GAD) antibodies are elevated.Antithyroid peroxidase (ATPO) or anti-thyroglobulin (ATG) antibodies are markedly elevated.
Hashimoto's encephalopathy
Rare but treatable autoimmune disorder that is commonly mistaken for Creutzfeldt-Jakob disease (CJD). Linked to chronic lymphocytic thyroiditis, this disease should be suspected with the presence of elevated antithyroid auto-antibodies.Although this disorder is also a rapidly progressive dementia with many common features of CJD, it is distinguished by its fluctuating course and more common association with seizures. [98] [103] [104]Patients may be euthyroid, subclinically hypothyroid, hypothyroid, or hyperthyroid, but to make the diagnosis, patients must be treated so that they are in a euthyroid state. [102]Hashimoto's encephalopathy is a diagnosis of exclusion.As the antithyroid antibodies are not shown to be causative in Hashimoto's encephalopathy, other terms have been applied to this condition, such as non-vasculitic autoimmune inflammatory meningoencephalitis and corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis.These autoimmune-mediated disorders are very important to identify, as they are readily treatable with immunosuppression, such as with high-dose corticosteroids. [98] [105] [106] [107] [108] [102]
Thyroid dysfunction may be present.Antithyroid peroxidase (ATPO) and/or anti-thyroglobulin (ATG) antibodies are positive.Brain MRI (ADC and DWI sequences) does not show the abnormalities seen in CJD.
Acid-base and electrolyte disorders
When patients present with recent-onset dementia of unknown aetiology, a toxic-metabolic encephalopathy work-up should be done.Metabolic disturbances such as electrolyte imbalances can produce rapidly progressive dementia.
Potassium, sodium, calcium, or magnesium levels are abnormal.
Other metabolic conditions
Other metabolic conditions in the Creutzfeldt-Jakob disease (CJD) differential include childhood metabolic disorders that may present in adults as dementia such as porphyria, adult-onset metachromatic leukodystrophy, orthochromatic leukodystrophies, and Kufs' disease.Systemic symptoms associated with these conditions are usually slower progressing but may be accompanied by rapid cognitive decline. [109]
Urine porphobilinogens are elevated during episodes of porphyria.Skin biopsy with electron microscopy is recommended for Kufs' disease diagnosis.Urine arylsulfatase levels are depressed in metachromatic leukodystrophy.Serum long-chain fatty acids are elevated in adrenal leukodystrophy.
Vitamin B1 deficiency
When patients present with recent-onset dementia of unknown aetiology, a toxic-metabolic encephalopathy work-up should be done.Metabolic disturbances such as certain vitamin deficiencies or rapid sodium shifts (causing extrapontine myelinolysis) can produce rapidly progressive dementia.A thiamine (vitamin B1) deficiency should be urgently considered in patients who are nutritionally deprived with neurological signs.Inadequate thiamine in the nervous system can lead to Wernicke's encephalopathy, which presents with nystagmus, ataxia, and memory loss.
Erythrocyte thiamine level is low.Brain MRI (T2-weighted, FLAIR, DWI, and ADC) may show abnormalities (restricted diffusion) in the mammillary bodies, thalami, periaqueductal white matter, and/or tectum. MRI findings in vitamin B1 deficiency have some overlap with those in sCJD, including restricted diffusion in the thalamus and other deep nuclei.
Vitamin B3 deficiency
Deficiencies of niacin or vitamin B3 (or the amino acid tryptophan, which is converted into niacin), may result in pellagra, which may present as a triad of dermatitis, diarrhoea, and dementia.Although the onset of pellagra is more insidious (death within a few years), it should be considered in nutritionally compromised (particularly low-protein intake) patients with dementia.
Nicotinic acid metabolites in the urine can confirm diagnosis; patients are treated with niacin supplements.
Vitamin B12 deficiency
In general, all patients with dementia should be tested for vitamin B12 levels, as this condition can respond to treatment. [110]
Low serum vitamin B12.The hallmark of diagnosis is the presence of a macrocytic anaemia with macro-ovalocytes in the peripheral blood smear.
Vitamin E deficiency
Vitamin E deficiencies can occur in people who are unable to absorb or metabolise fat-soluble vitamins.In rare cases, it is caused by an autosomal recessive mutation in the alpha-tocopherol transfer protein gene. This deficiency can cause ataxia and other movement disorders such as dystonia. It is rarely rapidly progressive and often presents similarly to Friedreich's ataxia.When it is diagnosed early, treatment with vitamin E can prevent progression. [111]
Serum vitamin E level is low.
Wilson's disease
Wilson's disease is due to an autosomal recessive mutation that hinders copper metabolism.The accumulation of copper in the tissues eventually causes dementia and liver disease, and generally presents in the teenage years, but almost always in patients <50 years of age.Although not rapidly progressive, it is important to consider this in younger adults with cognitive, behavioural, and/or movement disorder, as it is very treatable. [112] [113]
Serum and urine copper elevated.Blood ceruloplasmin is low.
Heavy metal intoxication
Heavy metal intoxication, especially with acute exposure, can lead to rapid cognitive decline.In contrast to rapidly progressive dementias, which progress over weeks to months, these encephalopathies can progress within hours to days.Patients being treated with bismuth (a metal used to treat GI disorders) should also be tested for toxicity. Often mistaken for Creutzfeldt-Jakob disease (CJD), bismuth intoxication can cause ataxia, apathy, and eventually myoclonus, speech problems, and change in mental status. If not treated, this condition can lead to permanent tremors and/or death. [114] [115] [116] [117]
Patients should be screened for arsenic, mercury, aluminium, lithium, bismuth, and lead toxicities.
Hepatic encephalopathy
Hepatic encephalopathy should be clinically easy to distinguish from Creutzfeldt-Jakob disease (CJD) because of presence of severe underlying liver disease.
Serum lactate and ammonia elevated.The EEG in hepatic encephalopathy may show periodic sharp waves similar to CJD.
HIV-related mental status changes
One fourth of AIDS patients eventually develop a neurological condition such as AIDS-dementia complex, HIV encephalopathy, or HIV-associated dementia. Therefore, all patients with rapidly progressive dementias should consider HIV testing. [60]Patients generally do not present with the combination of cognitive, motor, vision, and behavioural abnormalities as seen in CJD, but there is some overlap.
HIV 1 and 2 antibody screen is positive.Brain MRI does not show features consistent with CJD on diffusion imaging.
Syphilis
Spirochete infections are an unusual but treatable cause of dementia. Patients should be tested for Treponema pallidum or neurosyphilis, as cognitive dysfunction is a late complication of syphilis. [118]Patients generally do not present with the combination of cognitive, motor, vision, and behavioural abnormalities as seen in CJD, but there is some overlap. Also, they generally do not have rapidly progressive dementia.
CSF VDRL test is reactive.FTA-ABS test is reactive.Brain MRI does not show features consistent with CJD on diffusion imaging.
Lyme disease
Lyme disease is an infection caused by a tick bite containing the spirochete Borrelia burgdorferi. Neurological and psychiatric manifestations in this systemic infection occur with neurological involvement. [119]Although rarely reported as a rapidly progressive dementia, it should still be considered, as it is readily treatable. [120] [121] [122]Typically presents as a skin lesion indistinguishable from erythema migrans, and is principally found in the southeast and south central regions of the US.
B burgdorferi antibody elevated above index positive values.
Whipple's disease
Whipple disease, a rare bacterial infection caused by Tropheryma whippelii, interferes with many body systems and can manifest as a neuropsychiatric syndrome.Typically occurring at around 50 years of age, this condition predominantly affects men and can vary in its clinical presentation. Most commonly, patients present with gastrointestinal disturbances, cognitive impairment, and problems walking.May be mistaken for progressive supranuclear palsy due to the behavioural and eye movement abnormalities. [123]Once Whipple disease is diagnosed, patients can be treated with antibiotics. [124] [125]
Jejunal biopsy indicates presence of foamy macrophages.Tropheryma whippelii PCR of CSF positive.
CNS malignancy
Several malignancies can cause rapidly progressive dementias.Primary cancers that can mimic Creutzfeldt-Jakob disease (CJD) include primary CNS lymphoma, intravascular lymphoma, and gliomatosis cerebri.These conditions may present with many features of CJD and may be clinically indistinguishable.
CSF cytology and flow cytometry demonstrate abnormal cells (CNS lymphoma).Patients should be screened with brain MRI (with and without contrast); CT scans of the chest, abdomen, and pelvis with contrast; whole-body PET scan; mammogram; and CSF and serum cancer screens.Obvious brain masses should be easily distinguishable from CJD. [110]
Psychiatric disorders
Many psychiatric disorders can present in adulthood or later in life, but do not have accompanying neurological abnormalities.Many patients who self-refer themselves to physicians because they think they have Creutzfeldt-Jakob disease (CJD) or another prion disease have anxiety or conversion disorders.
A thorough neurological examination to identify any true neurological abnormality should generally exclude a psychiatric disorder.Brain MRI showing abnormalities would generally not be consistent with psychiatric disease.

Prolactinoma

Non-functioning pituitary macro-adenomas
May be no differentiating signs or symptoms.
Mild prolactin level elevation (up to 4348 picomols/L [100 nanograms/mL or 100 micrograms/L]) in the presence of a large pituitary mass compressing the pituitary stalk ('stalk effect').Pituitary imaging demonstrates a large pituitary tumour with no proportion to the mild prolactin elevation.
Drug-induced hyperprolactinaemia
There may be a drug history of antipsychotic, neuroleptic, or antidepressant drugs.Metoclopramide, methyldopa, verapamil, oestrogens, H2 blockers, and reserpine may result in mild hyperprolactinaemia.
Prolactin evaluation after the patient stops the drug reveals decreasing levels.No pituitary pathology on sellar imaging.
Hypothyroidism
There may be weight gain, cold intolerance, dry skin, constipation, or lethargy. In mild or subclinical hypothyroidism, there may be no differentiating symptoms.
Prolactin evaluation after thyroid hormone replacement.TFTs reveal hypothyroidism.
Renal insufficiency
May be no clear differentiating signs or symptoms.
Prolactin evaluation after renal improvement.Elevated serum creatinine, reduced creatinine clearance.
Pregnancy
May be no initial differentiating signs or symptoms.
Pregnancy test is positive.
Polycystic ovarian syndrome
Hirsutism or acne may be present. May be no differentiating signs or symptoms as associated with mild prolactin elevation and menstrual disturbance.
Presence of ovarian cysts demonstrated on ultrasound.

Prostate cancer

Benign prostatic hyperplasia
The symptoms experienced by a patient with BPH can often be identical to those experienced by a patient with later-stage prostate cancer.Typically, with BPH the prostate feels rubbery with no palpable nodules. Hard nodules suggest malignancy.
A positive prostate biopsy is the most sensitive and specific test to differentiate between prostate cancer and BPH.
Chronic prostatitis
Chronic prostatitis manifests over an extended period of >3 months to several years' duration with symptoms of urinary frequency, dysuria, male dyspareunia, and occasionally haematospermia. The latter must be differentiated from prostatic carcinoma.
Microscopic examination of the expressed prostatic secretions may reveal the presence of leukocytes indicative of inflammation. Serum PSA is typically mildly elevated in chronic prostatis. In cases where clinical suspicion is high for chronic prostatitis, it may be useful to treat the patient with a course of antibiotics and repeat the PSA to assess for response prior to recommending prostate biopsy to rule out prostate cancer.

Pseudohypoparathyroidism

Pseudo-pseudohypoparathyroidism
Patients have Albright's hereditary osteodystrophy without symptoms or signs of PTH hormone resistance.
Serum calcium and PTH are normal.Normal response to exogenous PTH as measured by urine cAMP and urine phosphorous.Paternal inheritance of causative GNAS mutations (GNAS is the gene that codes for the guanine nucleotide-binding protein Gs-alpha).
Primary hypoparathyroidism
History of prior thyroid gland surgery, multiple transfusions, or Wilson's disease.Morphological features of DiGeorge syndrome may be present (hypertelorism, micrognathia, short philtrum with fish-mouth appearance, anti-mongoloid slant, telecanthus with short palpebral fissures).Deafness or blindness suggestive of mitochondrial disease.May be associated with mental retardation and delayed development.
Parathyroid hormone levels are low with low serum calcium and 25-hydroxyvitamin D levels.Serum magnesium may be low or elevated.
Secondary hyperparathyroidism
Patients may have chronic kidney disease with fatigue, anorexia, dyspnoea, and oedema.Patients with vitamin D deficiency may have signs of rickets.
Serum creatinine is elevated with elevated PTH levels produced by decreased calcium and decreased 25-hydroxyvitamin D levels.
Vitamin D deficiency
Symptoms and signs of rickets: hypotonia, bone pain and tenderness, muscle weakness, bow legs and knob knees, Harrison's groove, pigeon deformity of the chest, and kyphoscoliosis.
Low 25-hydroxyvitamin D levels are diagnostic.
Fanconi's syndrome
Causes include sickle cell disease or chemotherapy identified in the history.
High urine calcium excretion without elevation of serum phosphate.Generalised aminoaciduria and glucosuria.The response of urinary cAMP and phosphate to human PTH (hPTH) is normal.
Fluorosis
Symptoms of bone pain.
Serum phosphorous is low to normal.Patients have increased bone density.The response of urinary cAMP and phosphate to hPTH is normal.
Osteopetrosis
Family history of osteopetrosis is present.The infantile form produces growth retardation, failure to thrive, and nasal stuffiness due to malformation of the mastoid and paranasal sinus.Skull deformities can produce cranial nerve entrapment or hydrocephalus.The adult form is milder and may be asymptomatic, or produce increased susceptibility to fractures.Nerve damage produced by bone fractures can cause blindness, facial paralysis, or deafness.
Serum phosphorous is low to normal.Patients have abnormally high bone density.The response of urinary cAMP and phosphate to hPTH is normal.
Osteosclerosis
No distinguishing clinical features.
Serum phosphorous is low to normal.Patients have abnormally high bone density.The response of urinary cAMP and phosphate to hPTH is normal.
Familial brachydactyly
Isolated abnormalities of the hand.
X-ray reveals shortening of the middle phalanx of all digits.Serum calcium and phosphorous are normal.The response of urinary cAMP and phosphate to hPTH is normal.
Prader-Willi syndrome
Patients have poor muscle tone and hyperphagia with a constant feeling of hunger.
Genetic testing identifies the causative mutations on chromosome 15.Serum calcium and phosphate levels are normal.The response of urinary cAMP and phosphate to hPTH is normal.
Acrodysostosis
Features of the head and face include brachycephaly, a hypoplastic 'pug' nose, maxillary hypoplasia, an open mouth, and epicanthal folds.
Serum calcium and phosphate levels are normal.The response of urinary cAMP and phosphate to hPTH is normal.
Turner's syndrome
Diagnostic morphological features include low-set or malrotated ears, down-sloping eyes, ptosis or hooded eyes, and low posterior hairline. A high-arched palate is also seen.
Karyotype reveals 10% or more of the cells with complete or partial loss of a sex chromosome.

Pseudotumor cerebri

Intracranial structural anomalies
May be clinically indistinguishable from PTC.
Intracranial pathology will be readily evident on MRI or magnetic resonance venogram of the brain, and these procedures can aid in differentiating between anomalies.Brain tumours, venous sinus thromboses, meningiomas infiltrating the venous sinuses, and other space-occupying lesions severe enough to cause increased intracranial pressure and papilloedema are usually obvious on neuroimaging. Cryptic arteriovenous malformations or dural fistulae with high flow may overload venous return and increase intracranial pressure.

Psittacosis

Atypical pneumonia
There are no differentiating signs/symptoms. Can be caused by many different organisms.
Serology, culture, or PCR for organism such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, or Legionella pneumophila
Sepsis
There are no differentiating signs/symptoms. Can be caused by many different organisms.
Blood cultures for gram-positive and gram-negative organisms, including facultative and fastidious organisms; viral cultures.
Multiple organ failure
There are no differentiating signs/symptoms. Can be caused by many different organisms.
Blood cultures for gram-positive and gram-negative organisms, including facultative and fastidious organisms; viral cultures.
Infective endocarditis
A history of intravenous drug abuse.
Serial cultures for typical bacteria such as Streptococcus and Staphylococcus involved in endocarditis; other organisms require special culture, such as Aspergillus, Brucella, Coxiella, and HACEK bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella species, and Kingella species).
Myocardial infarction
Chest pain.
The rise and fall of cardiac biomarkers such as troponin and creatine kinase (MB fraction) are important in the diagnosis, as is a serial change in the ECG. However, these do not distinguish the aetiological cause that includes an infectious pathogen, as most biomarkers would not be considered.
Tonsillitis
There are no differentiating signs/symptoms. Can be caused by many different organisms.
Oropharyngeal swab test for group A and beta haemolytic Streptococcus.
Hepatitis
There are no differentiating signs/symptoms. It can be caused by many different aetiologies.
Serology for hepatitis A to E (>95% of viral causes), and for CMV and HSV, as these are more common pathogens. Serology for EBV is less common in the setting of systemic disease.
Fever of unknown origin
A comprehensive history of exposure to others who are ill, travel to a tropical or developing country, and recent treatment. Physical examination may reveal skin rash, lymphadenopathy, bites, skin discoloration, etc.
Extensive testing is required and includes serology, blood cultures, and specialised tests for immune function.

Psoriasis

SLE
Sub-acute SLE may have clinical features of psoriasis, but plaques are less scaly and not lamellar.
Skin biopsy, including direct and indirect immunofluorescent tests, will confirm SLE.
Pityriasis rosea
Lesions may show features of guttate psoriasis but are in a characteristic Christmas tree-shaped distribution.Usually subsides within 8 weeks.
Clinical diagnosis is usually sufficient.
Seborrheic dermatitis
Scaly eruptions limited to scalp, eyebrows, paranasal region, ears, and chest.Scales are fine, not lamellar.
Skin biopsy shows dermatitis instead of psoriasis.
Mycosis fungoides
Very itchy and less scaly.Does not involve nails or joints. Usually not on scalp or ears.
Skin biopsy shows atypical lymphocytes and Pautrier abscess.
Diaper dermatitis
Oozy, weepy, and less scaly. Only in diaper region.
Clinical diagnosis is usually sufficient.
Onychomycosis
Only involves nails.
Culture of nail shows fungus.
Squamous cell cancer/actinic keratosis
Not as scaly, or in the case of actinic keratosis, fine scales may be present.Squamous cell cancer is limited to a few lesions.
Skin biopsy shows proliferating atypical squamous cells.
Eczema
Extremely itchy.Mostly oozy, crusted with lots of scratch marks.
Skin biopsy shows dermatitis instead of psoriasis.
Lichen planus
Usually limited to wrists and limbs. Oral mucosa is more likely to be involved than in psoriasis.Lesions are thick and without scaly or desquamated appearance.
Skin biopsy shows lichenoid lymphocyte infiltrates under epidermis.
Lichen simplex chronicus
Usually limited to a few areas easily reached by hands.Lesions are thick and mostly without scaly or desquamated appearance
Skin biopsy shows chronic dermatitis with epidermal acanthosis.
Subcorneal pustular dermatosis
Pustular lesions are subcorneal and in annular/serpiginous forms, present on the abdomen, axillae, and groin.
Culture of pustules shows no bacteria. Skin biopsy shows predominantly neutrophilic perivascular infiltrate; minimal spongiosis.

Psoriatic arthritis

Rheumatoid arthritis (RA)
A symmetric polyarthritis commonly affecting the small joints of the hands and feet.RA does not affect the lumbar spine or sacroiliac joints.Dactylitis is not a feature.
Rheumatoid factor and anticyclic citrullinated peptide antibodies may be positive.Hand x-rays reveal typical erosive changes at the margins of the joint, affecting the subchondral bone first and later progressing to cause joint space narrowing.
Gout
History of an acute and relapsing course with resolution of the synovitis within 7 to 14 days should raise the suspicion of possible gout.Swelling, effusion, warmth, erythema, and/or exquisite tenderness of the involved joint(s).Most commonly involved joints are in the feet, especially the first metatarsophalangeal, tarsometatarsal, and ankle joints.The pattern is usually monoarticular or oligoarticular (<4 joints). Can be polyarticular, affecting multiple joints in the hands and feet, especially in elderly people.Tophi may be present over extensor surface joints, especially the elbows, knees, and Achilles tendons. May also be evident over dorsal aspects of hands and feet, and in helix of the ears.
Synovial fluid examination will reveal strongly negative birefringent, needle-shaped crystals under polarised light.
Erosive osteoarthritis
Occurs most commonly in middle-aged women.Affects the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints of the fingers only.
Plain film x-rays will show typical changes of osteoarthritis involving the DIP and PIP joints with associated marginal or central bone erosions resulting in the characteristic gull-wing deformity.
Reactive arthritis
Recent exposure to certain gastrointestinal and genitourinary infections, particularly Chlamydia species, Campylobacter jejuni, and Salmonella enteritidis.Oligoarthritis, commonly affecting weight-bearing joints. May also have inflammation at the site of tendon insertion and dactylitis (whole-digit inflammation).Extra-articular manifestations such as conjunctivitis, urethritis, and stomatitis may be present.
X-rays may show soft-tissue swelling.Urine screen for Chlamydia trachomatis may be positive.
Mycobacterial tenosynovitis
Dactylitis-like swelling of a single digit may be observed.Mycobacterium tuberculosis and atypical mycobacteria have both been implicated.
Synovial biopsy and culture will most commonly isolate a rapidly growing mycobacterium from the tissue.
Sarcoid dactylitis
Dactylitis is observed in some patients with chronic sarcoid, especially those with cutaneous and osseous disease.Signs suggestive of underlying sarcoid usually present (e.g., cough, dyspnoea, wheezing, lymphadenopathy, skin lesions).
Chest-x-ray: hilar adenopathy and/or features of interstitial lung disease.Plain film x-ray of the hands and feet may show cystic bone lesions in the phalanges.Biopsy of suspicious skin lesion will reveal non-caseating granulomas.

Psychogenic polydipsia

Diabetes insipidus
Difficult to differentiate clinically.The defect may be central (low ADH secretion) or renal (low renal response to ADH). [35] [39] Hence, before a water restriction test, central diabetes insipidus (DI) and PPD can seem similar (low ADH and dilute urine). Concomitant PPD and DI have been reported. [40]Central DI may be congenital or acquired and may be associated with other pituitary hormone abnormalities.
Serum sodium is elevated.DI is also associated with low urine concentration before a water restriction test, as with PPD. ADH concentration depends on whether the defect is central DI (low ADH secretion) or renal DI (low renal response to ADH). [35] [39]Inability to concentrate urine presents following a water deprivation test in both central and renal DI.Adequate urine concentration achieved following vasopressin administration in central DI.
Diuretics
Thiazide diuretics are the most common cause of hypovolaemic or euvolaemic hyponatraemia. [44]Mechanisms include potassium loss, which contributes to a sodium shift to the intracellular compartment, and volume loss, which stimulates ADH secretion, thereby promoting water retention.Loop diuretics are less likely to cause hyponatraemia. A possible reason is that they wash out solute from the renal medulla, which reduces interstitial osmolality and the driving force for water reabsorption from the tubule.
Clinical diagnosis.Trial of discontinuing causative medication: hyponatraemia resolves.
Cerebral salt wasting
Produced by a range of intracranial pathologies, including head injury, intracranial surgery, subarachnoid haemorrhage, stroke, and brain tumours. The intracranial pathology causes excessive urinary sodium loss, but the mechanism of the effect is unknown.Physical signs include those associated with severe hyponatraemia or intravascular volume depletion.
Urine sodium level: >20 mmol/L (>20 mEq/L).Urine osmolality: low or normal.Serum osmolality: <280 mOsm/kg H2O.
Pseudohyponatraemia
Pseudohyponatraemia (isotonic hyponatraemia) is an artifact produced by high serum lipid or protein levels. The most common cause of high protein levels is multiple myeloma; this diagnosis is already known in most patients.
Hyponatraemia in the presence of a normal serum osmolality.
Syndrome of inappropriate ADH secretion
Difficult to differentiate clinically.May be caused by some drugs, such as diuretics, carbamazepine, oxcarbazepine, or fluoxetine (and other selective serotonin-reuptake inhibitors). [45] [46] [47] Reducing dose or switching to another medication helps correct the deficit.CNS causes include head injury, intracranial surgery, subarachnoid haemorrhage, meningitis, brain abscess, stroke, and ADH-secreting tumours (e.g., small cell lung cancer, pulmonary disease); SIADH may be idiopathic.
Hyponatraemia.Inappropriately elevated urine osmolality (>100 mOsm/kg H2O).Excessive urine sodium excretion (>20 mmol/L [>20 mEq/L] but often >40 mmol/L [>40 mEq/L]).Decreased serum osmolality.High plasma ADH.
Mineralocorticoid deficiency
Due to autoimmune destruction of the adrenal cortex (Addison's disease) or 21-hydroxylase deficiency producing a decrease in production of cortisol, aldosterone, and dehydroepiandrosterone.The decrease in aldosterone production causes increased sodium loss from the kidneys.Marked by poor skin turgor and dry mucous membranes.
Serum potassium: elevated.Urine sodium level: >20 mmol/L (>20 mEq/L).Serum osmolality: <280 mOsm/kg H2O.Morning serum cortisol: may be decreased.
Chronic alcohol use
Hx of alcohol ingestion. Other signs of chronic alcohol use include liver disease, pancreatitis, and CNS symptoms.Electrolytes are often abnormal. Prevalence rates of hyponatraemia in chronic alcoholic inpatients range from 5% to 17%. [48]
Clinical diagnosis.
Ecstasy (methylenedioxymethamphetamine or MDMA)
Designer drugs have been associated with hyponatraemia due to excess fluid intake, [49] as well as an SIADH-like syndrome. [50] Hyperthermia and hyponatraemia are 2 major syndromes most commonly reported as cause of death in fatal ecstasy use. [51]
Clinical diagnosis.
Beer potomania
A syndrome of hyponatraemia in connection with excess beer intake and low daily solute consumption. Seen in patients malnourished due to high carbohydrate/low sodium loads.
Clinical diagnosis.Urine osmolality is about 250 mOsm/kg H2O.Total urine output is reduced to 4 litres/day. [52]
Excessive solute
In the setting of hypertonic hyponatraemia, patients have normal total body sodium and a dilutional drop in the measured serum sodium due to the presence of osmotically active molecules in the serum causing water shift from the intracellular compartment to the extracellular compartment.
High plasma osmolality in the setting of hyponatraemia is usually due to excess solute from osmotic agents such as mannitol and glucose.Serum osmolality >295 mOsm/kg.
Salt-wasting nephropathy
Hx of renal disease.Due to intrinsic renal diseases that produce excessive sodium loss to the point of causing hypotension. Most often seen with tubular and interstitial kidney diseases. Examples include interstitial nephritis, partial urinary tract obstruction, and polycystic kidney disease.Clinical signs of volume depletion include decreased skin turgor, reduced jugular venous pressure, decreased blood pressure.
Urine sodium level: ≤20 mmol/L (≤20 mEq/L).Serum osmolality: <280 mOsm/kg H2O.Serum albumin: decreased.Serum creatinine: normal or elevated.
Nephrotic syndrome
Hx of longstanding diabetes mellitus, malignancy, SLE, HIV infection, multiple myeloma, connective tissue diseases, or amyloidosis; use of known causative medications (pamidronate, lithium, gold, penicillamine, or non-steroidal anti-inflammatory drugs, and, very rarely, interferon-alfa, heroin, mercury, or formaldehyde); foamy urine.Oedema of legs or whole body, Muehrcke's lines, xanthelasmas.
Serum albumin: decreased.Serum creatinine: normal or elevated.24-hour urine collection for protein: >3 g/24 hours proteinuria.
Chronic heart failure
Previous myocardial infarction, fatigue, decreased exercise tolerance, dyspnoea on exertion, orthopnoea, and paroxysmal nocturnal dyspnoea.Oedema, displaced cardiac apex, hepatojugular reflux, jugular venous distension, S3 gallop, pulmonary rales; hepatomegaly can also be present.
CXR: cardiomegaly, pulmonary oedema, pleural effusion.Electrocardiogram: anterior Q waves, bundle-branch block, atrial arrhythmias, ventricular arrhythmias, left axis deviation, ventricular hypertrophy.Echocardiogram: systolic and diastolic dysfunction, valve lesions, signs of pericardial injury or cardiomyopathy.
Cirrhosis
Hx of alcohol misuse, intravenous drug use, unprotected intercourse, obesity, blood transfusion, known hepatitis infection; fatigue, weakness, weight loss, or pruritus.Oedema, jaundice, ascites, collateral circulation, hepatosplenomegaly, leukonychia, palmar erythema, spider angiomata, telengiectasia, and jaundiced sclera can be present.
Serum ALT and AST: elevated with ALT to AST ratio ≥1 if hepatocellular damage; normal in cholestasis.Bilirubin: normal in compensated cirrhosis; elevated in decompensated cirrhosis.Serum albumin: decreased.Prothrombin time or INR: increased.Platelet count: decreased.

Pterygium

Pseudopterygium
Most often hx of previous infective, chemical, thermal, or traumatic injury to the cornea.May occur at multiple locations and is not restricted to the 3 and 9 o'clock (interpalpebral) positions.
Slit-lamp examination: reveals lesion to be adhesion of a fold of conjunctiva, which has occurred as a response to a previous peripheral corneal ulcer/inflammation.Lesion typically only fixed at its apex to the cornea so that a probe may be passed underneath its body at the limbus, while a true pterygium adheres to the underlying cornea throughout its length. Thinning of the underlying cornea may be seen at its head.
Pingueculum
Does not encroach on the cornea.
Slit-lamp examination: reveals exact extent and nature of lesion. A pingueculum is limited to limbus and conjunctiva and does not encroach onto the cornea.
Marginal keratitis
Associated with blepharitis. Infiltrate on corneal surface is separated by a clear zone from the limbus. Occur at 2, 4, 8, and 10 o'clock position. Does not have typical pterygium shape. Often superior and inferior.
Corneal swab/scraping: microscopy and culture positive for infecting organism, but infecting organisms are often not detected, as many cases are due to an inflammatory reaction to staphylococcal proteins.
Corneal micropannus
Hx of trachoma or lack of corneal oxygenation due to excessive contact lens wear.
Slit-lamp examination: reveals encroachment of fine blood vessels onto corneal surface.
Conjunctival carcinoma in sit
Rare. Does not have typical pterygium shape. Not restricted to the 3 and 9 o'clock (interpalpebral) positions and can occur at any position on the cornea.
Slit-lamp examination: gelatinous-appearing mass.Biopsy: cytological features of a squamous cell carcinoma, but the basal membrane of the epithelium remains intact.
Squamous cell carcinoma
Rare. Does not have typical pterygium shape. Not restricted to the 3 and 9 o'clock (interpalpebral) positions and can occur at any position on the cornea. May arise from a pterygium, carcinoma in situ, or de novo.
Slit-lamp examination: surface may appear keratinised and friable.Biopsy: well-differentiated squamous cell carcinoma with invasion of the basal membrane.

Pulmonary embolism

Angina, unstable
Typical cardiac chest pain is described as a retrosternal pressure or heaviness radiating to the jaw, arm, or neck.Pain may be intermittent or persistent.Differentiating risk factors include longstanding hypertension, diabetes, or hypercholesterolaemia.Can be difficult to differentiate from PE on the basis of signs and symptoms alone.
ST segment depression in contiguous leads on ECG.Normal troponin I or T. These tests may be elevated in PE. Negative diagnostic imaging study for PE.Critical stenosis of a coronary artery on coronary angiography.
Myocardial infarction, non-ST elevation (NSTEMI)
Part of acute coronary syndrome spectrum.Presents with central chest pain that is classically heavy in nature, like a sensation of pressure or squeezing.Examination findings are variable and range from normal to a critically unwell patient in cardiogenic shock.Often difficult to differentiate from PE in acute setting.
ECG does not show ST-elevation, but serum levels of cardiac biomarkers are raised.ECG may show non-specific ischaemic changes such as ST depression or T wave inversion.May see bilateral increased pulmonary vascular congestion on chest radiograph consistent with CHF.Elevated troponin I or T. These may also be elevated in the setting of PE.Regional wall motion abnormality of the left ventricle on echo.
Myocardial infarction, ST-elevation (STEMI)
Presents with central chest pain that is classically heavy in nature, like a sensation of pressure or squeezing.Examination findings are variable and range from normal to a critically unwell patient in cardiogenic shock.Often difficult to differentiate from PE in acute setting.
STEMI is diagnosed by persistent ST segment elevation in 2 or more anatomically contiguous ECG leads in a patient with a consistent clinical history.Elevated troponin I or T, can also be raised in PE.Regional wall motion abnormality of the left ventricle on echo.Critical stenosis of a coronary artery on coronary angiography.
Pneumonia, community-acquired
May be difficult to differentiate on the basis of signs and symptoms.Cough productive of purulent sputum.Fever above 39.0°C (102.2°F); generally higher than in PE. [62]
WBC count normally >11 x 10^9/L (>11,000/microlitre).CXR may show a focal opacity and other features of pneumonic consolidation. This can also be seen with PE.Sputum culture grows an organism known to cause pneumonia.Negative diagnostic imaging study for PE.
Bronchitis, acute
More insidious, subacute onset of symptoms than PE.Diffuse wheezes/rhonchi on pulmonary auscultation.Cough productive of purulent sputum.
Normal CXR. This can also be seen in PE.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
COPD, acute exacerbation
History of previous/ongoing tobacco use.Diffuse wheezes on pulmonary auscultation.Diffuse decrease in breath sounds on pulmonary auscultation.Increased expiratory phase of the respiratory cycle.PE may be present in 6% to 25% of patients with a COPD exacerbation of unknown cause. [63] [64]
Evidence of hyperinflation, flattened diaphragms, and increased retrosternal air on CXR.Incompletely reversible reduction in FEV1 and FEV1/FVC on spirometry.Normal troponin I and T. Normal brain natriuretic peptide (BNP).Normal right and left ventricular function on echo.RV strain with decreased RV function can be seen on ECHO in patients with pulmonary hypertension secondary to COPD. This can also be seen in PE.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
Asthma, acute exacerbation
Previous history of asthma/atopy.Diffuse wheezes on pulmonary auscultation.Diffusely decreased breath sounds on pulmonary auscultation.Prolonged expiratory phase of the respiratory cycle.
Normal chest radiograph. This can also be seen with PE.Reversible reduction in peak flow measurement (peak expiratory flow or FEV1).Normal troponin I and T and normal BNP.D-dimer, CT pulmonary angiogram, and V/Q scan normal.
CHF, acute exacerbation
May be difficult to differentiate solely on the basis of signs and symptoms.More insidious, subacute onset of symptoms than those generally seen with PE.Orthopnoea, paroxysmal nocturnal dyspnoea, and documented weight gain are common.Increased bilateral lower extremity swelling.Diffuse crackles on pulmonary auscultation.Elevated jugular venous pressure.Features of right-sided heart failure can occur in PE.
Increased pulmonary vascular congestion on chest radiograph with enlarged cardiac silhouette.Bilateral alveolar infiltrates on chest radiograph.Elevated BNP. This can also be seen in PE, but PE rarely results in BNP levels >1000 nanograms/L (>1000 picograms/mL). [51]Decreased LV function with a decreased ejection fraction on ECHO.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
Pericarditis
May be difficult to differentiate on the basis of signs and symptoms.Chest pain improves when sitting up and worsens when supine.
ST segment elevation in all leads on ECG.Electrical alternans on ECG.Normal chest radiograph. May see an enlarged cardiac silhouette.Elevated troponin I or T. This may also be seen with PE.Pericardial effusion on echo.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
Tamponade, cardiac
Difficult to differentiate on the basis of signs and symptoms.The Beck's triad of hypotension, muffled heart sounds, and elevated jugular venous pressure are classic features, although are not always present.Patients often complain of dyspnoea and chest pain.
Normal CXR. May see an enlarged cardiac silhouette.Pericardial effusion on echo with evidence of tamponade physiology is diagnostic.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
Pulmonary HTN due to chronic thromboembolic disease
History of PE; bruits over the lung fields (pulmonary flow murmurs) are present in 30% of cases.More insidious, subacute onset of symptoms than those generally seen with PE.Documented weight gain.Bilateral lower extremity swelling.
ECG findings can show right axis deviation, p-pulmonale, and/or possible right bundle branch block.Normal D-dimer/CXR.Ventilation-perfusion lung scintigraphy: one or more segmental-sized or larger unmatched perfusion defects.Pulmonary angiography: vascular webs or band-like narrowing, intimal irregularities, pouch defects, abrupt and angular narrowing, and proximal obstruction.
Pneumothorax
May be difficult to differentiate on the basis of signs and symptoms.History of recent trauma to the chest.Decreased breath sounds unilaterally on pulmonary auscultation.Hyperresonance on percussion of affected side.Deviation of the trachea away from the affected lung.
Loss of lung markings in the periphery with evidence of lung collapse on CXR.May see evidence of pneumothorax associated with a rib fracture on CXR.Normal D-dimer in the correct clinical setting or a negative diagnostic imaging study for PE.
Costochondritis
Presents with insidious onset of anterior chest-wall pain exacerbated by certain movements of the chest and deep inspiration.Point tenderness on palpation of costochondral joints (particularly the second to the fifth).
No specific diagnostic tests.Normal D-dimer or a negative diagnostic imaging study for PE.
Panic disorder
Sudden-onset anxiety, feeling faint, and palpitations.Recurrent, discrete period of intense fear/discomfort.Sense of apprehension can be manifested as fear of death or life-threatening illness.
Clinical diagnosis requiring formal psychiatric assessment.Normal D-dimer or a negative diagnostic imaging study for PE.

Pulmonary regurgitation

Mitral stenosis
Malar flush, low volume pulse, a tapping and undisplaced apex beat, and loud S1 with an opening snap.The murmur is rumbling and mid-diastolic.
CXR: pulmonary oedema, enlarged left atrium, and mitral valve calcification.ECG: can present with atrial fibrillation. RVH may also be present.Echocardiogram: diagnostic for mitral stenosis.
Aortic regurgitation (AR)
In mild AR the murmur is early diastolic, and increases in duration to holodiastolic in severe AR.A diastolic murmur may be absent in acute AR.
CXR: may show cardiomegaly in the leftward and inferior direction in chronic AR.ECG: may show non-specific ST-T wave changes, left axis deviation, or conduction abnormalities.Echocardiogram: visualisation of the origin of regurgitant jet and its width; detection of cause of aortic valve pathology.
Atrial myxoma
The murmur is mid-late diastolic, and changes in character and intensity with alterations in position.
Echocardiogram: visualisation of a mass, usually attached to the interatrial septum or free wall of the atrium.

Pulmonary stenosis

Innocent murmur
Asymptomatic.On auscultation, systolic murmur, usually softer and shorter compared with PS, no ejection click.
Echo with colour Doppler: normal cardiac anatomy.
Straight back syndrome
On auscultation, no ejection click but systolic right ventricular (RV) outflow track murmur along left upper sternal border.
Echo with colour Doppler: normal cardiac anatomy.Lateral CXR: abnormally straight spinal curve.
Idiopathic dilation of pulmonary artery
On auscultation, softer systolic murmur.
Echo with colour Doppler: morphologically normal pulmonary valve, dilated pulmonary artery.
Pulmonary artery stenosis
On auscultation, mid-to-late systolic murmur, radiating to the back and lateral lung fields, no ejection click.
Echo: stenotic pulmonary artery.
Aortic valve stenosis
On auscultation, systolic ejection murmur in upper right sternal border, radiating into carotids and left ventricular apex.
Echo with colour Doppler: stenotic aortic valve.
Atrial septal defect (ASD)
On auscultation, systolic RV outflow track murmur of functional PS, wide and fixed splitting of S2, no ejection click.
Echo: morphologically normal pulmonary valve but abnormal atrial septum; colour Doppler: left-to-right shunting.
Ventricular septal defect
On auscultation, pansystolic regurgitant murmur typically at lower sternal border; can be difficult to distinguish from PS murmur.
Echo with colour Doppler: septal blood flow.
Ebstein's anomaly
Active pre-cordium; on auscultation, softer systolic murmur at lower left sternal border, sometimes 'quadruple' rhythm.
CXR: cardiomegaly, decreased pulmonary vascular markings.ECG: reduced voltage, right bundle branch block, right atrial enlargement; echo: inferior displaced septal leaflet, redundant anterior leaflet of tricuspid valve.
Tetralogy of Fallot
Cyanosis more pronounced than in PS; usually no ejection click as stenosis lies below level of valve or is due to small pulmonary annulus.
CXR: decreased pulmonary vascular markings, uptilted right ventricular apex.Echo with colour Doppler: aortic override, ventricular septum defect.
Pulmonary valve atresia with intact ventricular septum
Progressive cyanosis; on auscultation, no PS murmur as all the pulmonary blood flow is via ductus arteriosus.
Echo with colour Doppler: atresia of pulmonary valve, blood flow via ductus arteriosus.

Pulmonary tuberculosis

Community-acquired pneumonia
Signs of lobar or atypical pneumonia including crackles and dyspnoea. Generally, shorter duration of symptoms compared with TB. If there is doubt, consider treating for bacterial pneumonia first (without using fluoroquinolones or other antibiotics with significant antituberculous activity) and assess for response.
Sputum examination with presence of bacteria other than normal flora.
Lung cancer
TB and lung cancer may co-exist; malignancy may erode granulomas. Despite acid-fast bacilli (AFB) in sputum, if features suggest cancer (e.g., irregular cavities) or lung abnormalities progress in patients on antituberculous treatment, further evaluation for cancer should be pursued. [34]
Sputum cytology; CT of the chest; tissue biopsy.
Non-tuberculous mycobacteria (NTM)
Mycobacterium avian complex and M. kansasii may both present as cavitary lesions. Patient risk factors for TB may point to most likely diagnosis.
If sputum AFB culture is positive, DNA probe may be used for species identification. Similarly a nucleic acid amplification test (NAAT) that is negative for TB on a smear-positive sputum (95% sensitivity) makes M. tuberculosis less likely. NTM is more common in patients with underlying lung disease.
Fungal infection
Potential fungi include histoplasmosis, coccidioidomycosis, and blastomycosis. Travel history may help narrow the differential diagnosis.
Sputum culture and serum antibody titres positive for fungal infection and negative for M. tuberculosis.
Sarcoidosis
Other features of sarcoidosis, such as intrathoracic lymphadenopathy and arthralgias, may be present.
Sputum culture will be negative in sarcoidosis.

Pyloric stenosis

GORD
Emesis similar to that in pyloric stenosis may occur after feeding but is not forceful, and it is usually small in volume and effortless. The emesis can rarely contain blood.GORD can lead to failure to thrive, chronic lung disease, oesophagitis, and oesophageal strictures. [41] Symptoms usually begin by 6 weeks of life but resolve by 2 years of age. [42]
Barium swallow and radionuclide scan may show oesophageal reflux, and endoscopy may show superficial oesophageal ulcerations or inflamed mucosa. [41] Overnight oesophageal pH monitoring showing low pH is the diagnostic standard.Electrolytes are usually normal, although chloride may be slightly depressed due to emesis. [43]
Over-feeding
Infants will not have difficulty gaining weight.
Can be determined by estimating appropriate feeding volumes and comparing them with actual volumes.Chemistry panel and ultrasonographic measurements of pyloric muscle thickness and channel length will be normal.
Malrotation
Many cases present in adulthood. [44]The key symptom is bilious emesis, unlike non-bilious emesis seen in pyloric stenosis.
Upper GI fluoroscopic contrast study will show duodenojejunal junction not crossing mid-line. If the mid-gut is volvulated around its mesentery, the classic corkscrew appearance of contrast flowing to the jejunum will be seen. [44]
Acute infectious diarrhoea
Diarrhoea generally follows vomiting. Diarrhoea is seldom seen in pyloric stenosis, which usually presents with constipation.
Infants with infectious diarrhoea can have severe volume depletion and electrolyte disturbances similar to those seen in pyloric stenosis.Stool cultures may show Escherichia coli, Campylobacter jejuni, Salmonella, or Shigella.
Food allergy
Clinical features are vomiting and diarrhoea for the first 3 months of life.Bloody diarrhoea can be seen due to the development of allergic colitis.
In addition to dietary history, diagnosis is based on exclusion of allergic agents.
Antral web
Typically, diagnosed after a long period of symptoms. Diagnosis can occur up to 5 years of age.
Barium upper GI imaging is diagnostic in 90% of patients, showing double bulb (normal duodenal bulb and proximal antral chamber between the web and the pylorus). [45]
Duodenal atresia
Seen in neonates.Bilious emesis is seen in 85% of patients, as most atresias are distal to the ampulla of Vater. [44] Pyloric stenosis patients present with non-bilious projectile emesis.One third of infants with this diagnosis have Down's syndrome.
Antenatal ultrasound may show polyhydramnios, fluid-filled stomach, and proximal duodenum.Classic sign is a double bubble on an abdominal x-ray. [44]
Jejunoileal atresia
Will cause bilious emesis, unlike non-bilious emesis seen in pyloric stenosis. [44]
Diagnosed with contrast radiographic study. [44]
Pyloric atresia
Presents as non-bilious emesis in neonates upon feeding.Can be seen as epidermolysis bullosa-pyloric atresia syndrome in rare cases. [44]
GI contrast study shows gastric outlet obstruction. [44]

Rabies

Herpes simplex virus infection
Does not show the relapsing/remitting pattern of mental lucidity seen in rabies.
CSF is bloody.HSV is detected in CSF by PCR with >95% sensitivity.
Enterovirus meningoencephalitis
Fall seasons may overlap. May show similar profound dysautonomia with cardiomyopathy.
Enteroviruses are detected in CSF by PCR with >95% sensitivity.
West Nile virus encephalitis
History of a mosquito bite.Generally shows more parkinsonian findings or general body rigidity than rabies.
West Nile virus-specific IgM in CSF is diagnostic.
Other arbovirus encephalitides
History of a mosquito bite.Generally show more parkinsonian findings or general body rigidity than rabies.
Serum anti-arboviral antibodies are positive.
Rocky Mountain spotted fever and rickettsial encephalitis
Petechial rashes and eschars are present
WBC count usually low.Rocky Mountain spotted fever and other rickettsial serologies are diagnostic.
Japanese encephalitis
Parkinsonian symptoms are common.Patients develop hyperreflexia.
Presence of Japanese encephalitis virus RNA in tissue, blood, or CSF is diagnostic.Japanese encephalitis virus antibodies may be detected in CSF or serum.
Guillain-Barre syndrome
Acute flaccid paralysis is similar to paralysis seen in rabies, especially paralytic rabies.Sphincter involvement is rare.There is no fever.
CSF shows elevated protein with a normal cell count (albuminocytological dissociation).Nerve conduction studies show slowing of nerve conduction velocities.
Acute disseminated encephalitis
Aerophobia and hydrophobia are absent, but other clinical features are similar to rabies.
Brain MRI shows white matter lesions.
Tetanus
Aerophobia, hydrophobia, and mental state changes are absent.The main sign is trismus (which results in a grimace described as 'risus sardonicus,' or sardonic smile) associated with muscle rigidity, spasms, respiratory embarrassment, dysphagia, or autonomic dysfunction.
Detection of tetanus toxin in plasma or clostridial culture from wound swab.CSF is normal.
Bartonella encephalitis
Associated with lymphadenitis.
Bartonella serologies are diagnostic.
Delirium tremens
History of chronic alcohol use and either reduction or cessation of drinking before presentation.Prodromal illness is absent.Fever is rare.
The diagnosis is clinical.
Cocaine overdose
History of cocaine use.
Cocaine may be detected in urine, blood, or gastric contents. The half-life in blood is short.
Amfetamine overdose
History of amfetamine abuse.
Urine is positive for amfetamines.
Acute psychosis
Main symptoms are hallucinations, delusions, and thought disorder, possibly accompanied by agitation. The prodrome and physical manifestations of rabies are absent.Other clinical features depend on the cause.
No differentiating tests.

Raynaud's phenomenon

Normal response to cold
Normal hands can be mottled in cold. RP has classic pallor that is well demarcated.
No differentiating tests.
Cyanosis/cryoglobulinaemia
Blue digits in cold but no distal digital pallor.
Detection of circulating cryoglobulins.
Chilblains (perniosis)
Symptoms include pruritus, erythema, and ulceration.An acute response to cold temperatures but can be chronic.
No differentiating tests.
Acrocyanosis
There is no ischaemia (no pallor in this condition), which is characterised by non-paroxysmal, in most cases persistent, painless bluish-red symmetrical discolorations of the hands and often the feet. The history with lack of pallor (no well-demarcated white colour change). [1]
No differentiating tests.
Erythromelalgia
Usually provoked by heat.Characterised by painful red extremities, burning, and increased skin temperature of affected area. [1]
Thrombocytosis may be underlying cause.
Livedo reticularis
Lacy purple appearance of skin at extremities.Venous blood flow sluggish.Usually found on legs.
May be positive of antiphospholipid antibodies (e.g., anticardiolipin antibodies, lupus anticoagulant).
Carpal tunnel syndrome
Numbness and tingling of fingertips, with no distal digital pallor.Associated conditions may be present: pregnancy, hypothyroidism, diabetes, or rheumatoid arthritis.Positive Tinnel’s or Phalen’s test in carpel tunnel syndrome. Lack of colour change in carpel tunnel syndrome.
Nerve conduction studies: focal slowing of conduction velocity in the median sensory nerves across the carpal tunnel (necessary only if symptoms are severe or there is wasting of the thenar eminence).Elevated TSH, blood glucose, and serum abnormalities of other associated conditions may be present.
Cervical rib or other subclavian compression
May develop RP, but ischaemia is often positional with the arm above the head.
CXR may demonstrate cervical rib. Routine screening of mild RP would not require this investigation, as it would be performed only if there was a high index of suspicion.
Subclavian steal syndrome
Symptoms/signs of peripheral ischaemia usually present unilaterally.Dizziness, syncope, and vertigo common.
Duplex ultrasonography demonstrates retrograde blood flow and occlusive lesions of vascular architecture.

Reactive arthritis

Ankylosing spondylitis (AS)
Similar spinal involvement to reactive arthritis (ReA), but in a more symmetrical fashion, particularly in the sacroiliac joints.
Axial x-rays reveal syndesmophytes (ossification of spinal ligaments forming bony bridges between vertebrae) that tend to be marginal rather than non-marginal. Evidence of 'bamboo' spine is indicative of AS. AS has less prominent peripheral joint involvement than ReA.
Psoriatic arthritis
The 2 conditions can be difficult to distinguish particularly in patients with psoriatic arthritis who do not have psoriasis and in both groups of patients with skin involvement. Skin lesions can appear grossly similar and are histologically identical to those of ReA. In psoriatic arthritis, distal interphalangeal (DIP) joints are more commonly affected.
Hand x-rays reveal erosion of one end of DIP joint with expansion of the base of the adjacent metacarpal; resorption of terminal phalanges.
Rheumatoid arthritis (RA)
A symmetric polyarthritis commonly affecting the small joints of the hands and feet. RA does not affect the lumbar spine or sacroiliac joints.
Rheumatoid factor and anti-CCP (cyclic citrullinated peptide) antibodies may be positive in RA. Hand x-rays reveal typical erosive changes.
Rheumatic fever
Rheumatic fever is associated with the upper respiratory system before the onset of arthritis. Fevers are common in both entities. Rheumatic fever starts as an acute migratory arthritis involving both upper and lower extremities. There is no involvement of the axial spine, including the sacroiliac joints. Post-streptococcal ReA is an acute arthritis associated with antecedent streptococcal infection in patients not fulfilling the Jones criteria for acute rheumatic fever. Post-streptococcal ReA probably has lower-extremity predominance and, therefore, should be included in the differential diagnosis of patients with lower-extremity arthritis. It is not clear if this is a separate disease or a forme fruste of rheumatic fever.
Antistreptolysin-O antibodies and throat culture/rapid antigen test for group A streptococcus may be positive.
Adult-onset Still's disease
Patients with both Still's disease and with ReA can both experience fevers. However, the fever in Still's disease is described as double quotidian (2 spikes of fever a day). A characteristic evanescent, salmon-coloured rash occurs at the same time as the fevers in Still's disease.
May see leukocytosis and thrombocytosis on FBC count, elevated LDH, abnormal LFTs and elevated serum ferritin. Hand x-rays may show intercarpal and carpometacarpal joint space narrowing without erosions.
Disseminated gonococcal disease
The arthritis of gonococcal disease occurs as an acute migratory polyarthritis with tenosynovitis, often involving the hands. Another feature of gonococcal infection includes small, painless, maculopapular, pustular or vesicular lesions on an erythematous base involving the extremities.
Genitourinary culture for Neisseria gonorrhoeae.
Arthritis associated with inflammatory bowel disease (IBD)
The presence of documented IBD distinguishes the arthritis associated with IBD from ReA.
There are no differentiating tests.
Gout
Patients have more DIP joint involvement in gout. Patients may also have uric acid tophi, for example, in the pinna of the ear.
Crystal in the synovial fluid of affected joints.
Septic arthritis
Affects single joints in most cases. The affected joint is often swollen, erythematous and warm, and patients may have a fever.
Culture of the organism from the synovial fluid of an affected joint. Often, the cell count of synovial fluid exceeds 50,000 per mm^3, with more than 75% polymorphonuclear leukocytes. May also have positive blood cultures.
Post-viral arthritis
Arthralgias are preceded by a influenza-like illness in parvovirus infection. A rheumatoid-like distribution (symmetrical small joint polyarthritis) of arthralgias is typical. Occasionally, patients may have a maculopapular rash.
In parvovirus B19 infection, may see positive serology; positive IgM within the first 6 weeks of exposure is diagnostic.
Lyme arthritis
Lyme disease produces a characteristic rash called erythema migrans at the site of the tick bite. Non-specific constitutional symptoms such as headache, fever and fatigue are common in Lyme disease. The arthritis can be migratory and often affects only 1 joint at a time, primarily large joints such as the knee.
Positive Lyme titre with Western blot.

Relapsed NHL

Hodgkin's lymphoma
Bimodal age distribution at diagnosis (peaks at mid-20s and mid-60s), pruritus, and alcohol-triggered pain. Very difficult to differentiate clinically.
Lymph node biopsy (Reed-Sternberg cells are characteristic). [29]
ALL
Acute onset, purpura, bleeding, and infection are key presenting symptoms.
Blood smear (blasts), bone marrow biopsy (blasts), flow cytometry, and immunochistochemistry (tumour cell markers), cytogenetics, PCR.
Infectious mononucleosis
A self-limiting condition that occurs in young adults (high school and university students). There is generally abrupt onset of symptoms including pharyngitis, rash, and myalgias.
Heterophile antibody test (monospot) positive, EBV titres elevated, polyclonal B-lymphocyte population on flow cytometry.
Hepatitis C (HCV)
History of IV drug use, HIV, multiple transfusions; abdominal pain, nausea, symptoms of liver disease and malaise; can be asymptomatic.
Antibody-HCV (enzyme-linked immunosorbent assay [ELISA]) or recombinant immunoblot assay, RT-PCR for HCV RNA.
Cytomegalovirus infection (CMV)
Immunocompromised host (e.g., post-transplant); cough, bone pain, visual symptoms, and diarrhoea are common presenting features.
CMV titres (elevated), CMV PCR, rectal biopsy for CMV.
Tuberculosis
Not always easy to differentiate clinically, but patient may have risk factors for tuberculosis (e.g., HIV positive, history of drug use, inadequate nutrition, inner city population), cough, malaise, and weight loss.
CXR, CT chest, purified protein derivative of tuberculin, acid-fast bacillus test, TB culture, pleural/peritoneal fluid analysis (in some cases), pleural biopsy (in some cases), bone marrow biopsy (in some cases).
HIV infection
Risk factors for sexually transmitted disease (e.g., multiple sexual partners, unprotected sexual intercourse), history of IV drug use, multiple transfusions before 1985, prior flu-like illness and rash.
ELISA (screen), Western blot (confirm), RT-PCR for HIV RNA (viral load) are diagnostic.
Syphilis infection
Consider risk factors for STD; prior genital chancre and rash.
Treponema-non-specific tests: rapid plasma reagin, Venereal Disease Research Laboratory (VDRL); Treponema-specific tests (fluorescent treponemal antibody absorption [FTA-ABS]; micro-haemagglutination Treponema pallidum [MHA-TP]) are diagnostic.
Sarcoidosis
Young or middle-aged, cough, dyspnoea, skin lesions, Bell's palsy, and malaise; may be asymptomatic.
CXR, CT chest (hilar adenopathy), bronchoscopy with biopsy of lymph nodes (non-caseating granulomas).
Rheumatoid arthritis
More common in females; joint symptoms (pain, swelling, heat, stiffness).
Rheumatoid factor (IgM antibody) elevated titre; ESR elevated; synovial fluid analysis.
Systemic lupus erythematosus (SLE)
Much more common in females; characteristic rash (may be butterfly type), photosensitivity, skin lesions, oral ulcers, myalgia, arthritis, and neurological symptoms.
ANA, anti-double-strand DNA, anti-Sm antibodies, abnormal FBC, proteinuria; American Rheumatology Association (ARA) criteria for diagnosis. [30]

Relapse Ewing sarcoma tumor

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Relapse soft tissue sarcoma tumor

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Renal artery stenosis

Essential hypertension
No specific signs or symptoms. More frequently causes milder hypertension.
Diagnosis of exclusion.
Acute kidney injury
No specific signs or symptoms. Can be associated with difficult-to-control hypertension and abnormal volume status regulation.
GFR is low.Urinalysis and sediment evaluation may show proteinuria, haematuria, cells, casts, or crystals.
Renal artery dissection
Difficult to differentiate clinically.Although fibromuscular dysplasia places patients at a greater risk of renal artery dissection, spontaneous dissection of the renal artery or the aorta (involving the renal arteries) may cause severe HTN and loss of kidney function.
Ultrasound, MR angiography, CT angiography, or conventional angiography will highlight an intimal flap.
Renal artery embolism
History of other vascular disease, possibly history of catheterisation, although it may occur spontaneously.
GFR may be reduced.Eosinophilia may be present.Lactate dehydrogenase level is commonly elevated.Urinalysis and sediment evaluation may show WBCs and eosinophils.
Chronic kidney disease
Patients with chronic kidney disease typically have difficult-to-control HTN and volume status, which may mimic RAS. Furthermore, diabetes and hypertension are both causes of chronic kidney disease as well as RAS.
GFR is typically reduced.Urinalysis and sediment evaluation often show markers of kidney damage such as proteinuria or cells, casts, or crystals.Kidney biopsy may demonstrate glomerular, tubular, or interstitial pathology.
Coarctation of the aorta
Blood pressure different in arms and/or legs.
Blood pressure in arms and legs demonstrates discrepancy.Echo, MRI, and aortography may highlight coarct.
Primary hyperaldosteronism
Resistant or accelerated HTN, adrenal adenoma.
Plasma potassium may be low while urine potassium may be high.Plasma aldosterone-to-renin ratio >20.Adrenal CT may highlight a unilateral mass or bilateral gland enlargement.Urine aldosterone is not suppressed after oral salt load.Adrenal venous sampling demonstrates non-suppressible hormone levels.
Cushing's syndrome
Moon face, buffalo hump, obesity, abdominal striae, possible history of corticosteroid administration.
High morning plasma cortisol after 1 mg dexamethasone at bedtime.Urinary cortisol levels are elevated.Adrenal CT demonstrates gland enlargement.Pituitary imaging may demonstrate adenoma.
Phaeochromocytoma
Resistant or accelerated HTN, possibly episodic hypertension.
Plasma-free metanephrines, urine metanephrines and catecholamines, and plasma normetanephrine are elevated.Adrenal CT and scintigrams may demonstrate a mass.
Vasculitis
Usually with systemic symptoms (e.g., fever, weight loss), progressive kidney failure.
Decreased GFR may be present.Urinalysis and sediment may show proteinuria and haematuria.Serological testing may be abnormal.

Renal cell carcinoma

Benign renal cyst
Typically asymptomatic.
Bosniak classification on imaging: low score (if questionable, interval change on imaging and/or pathology is distinguishing). [58]
Ureteric cancer
Gross haematuria more common.
Ureteroscopy: ureteric mass.
Bladder cancer
Gross haematuria more common. Dysuria.
Urine cytology: positive in up to 90% of patients with carcinoma in situ or high-grade tumours; positive in <33% of patients with low-grade transitional cell cancer.
Upper urinary tract urothelial tumour
Gross haematuria more common.
Gross pathology: transitional cell carcinoma histology.Cystoscopy: central renal mass (pelvis). [46]MRI: central pelvic /urethral location of mass.
Angiomyolipoma
Clinically indistinguishable.Often too small to present with palpable masses, and usually asymptomatic. May grow to cause pain and haematuria.
CT/MRI: small (<1 cm); characteristic features (particular fat distribution). If questionable on imaging, and especially if 1-3 cm in size, percutaneous biopsy indicated. [58]
Oncocytoma
Clinically indistinguishable.Typically asymptomatic; often small.
CT/MRI: small (1-3 cm), may have characteristic features (almost always solid, and non-enhancing). If questionable on imaging, percutaneous biopsy may be indicated. [58]
Secondary metastases
Symptoms consistent with other primary tumours may point towards secondary metastatic renal lesions. Symptoms from local disease burden less likely (the masses are generally smaller but multifocal). [57]
Presence of non-renal malignancy on any diagnostic test with non-enhancing renal masses makes metastases more likely, but if no progression of non-renal primary cancer is documented, there is less chance of renal metastases. [57] [61]
Congenital renal parenchymal abnormalities
Often no distinguishing symptoms or signs.
CT and MRI (especially the latter) can usually help distinguish.
Renal infarction
Clinical history of vascular risk factors may raise suspicion of infarction (especially poorly controlled hypertension/hypertensive crisis).
MRI: assesses kidney and determines likelihood of infarction.Magnetic resonance angiogram (MRA): assesses local vessels.
Renal infection
Clinical history of fever or sepsis.
FBC: leukocytosis.Blood culture: bacteraemia. Urine culture: bacteriuria.Serial imaging (CT/MRI) may be needed to ensure resolution of renal mass after treatment for infection.

Renal tubular acidosis

Respiratory alkalosis
Patients are most often asymptomatic.Patients with liver cirrhosis or pregnancy commonly have respiratory alkalosis.
The key to differentiating between RTA and respiratory alkalosis is the arterial blood pH. In RTA the pH is always low. When serum bicarbonate is low, an arterial pH of 7.37 or greater indicates the diagnosis is respiratory alkalosis.
Non-specific diarrhoea
Diarrhoea.
Patients differ from those with RTA due to the presence of a low urine pH and a large negative urine anion gap. Similar blood and urinary laboratory findings occur after the ingestion of ammonium chloride. The evidence of normal urinary acidification excludes RTA in these cases.
Diabetic ketoacidosis
History of ongoing treatment of diabetic ketoacidosis with insulin and large volumes of sodium chloride infusion.
The urine pH is low in acidosis here unless urine ketone excretion is extremely high.
Renal glycosuria
May be confused with Fanconi's syndrome. Patients with renal glycosuria exhibit glycosuria at normal serum glucose levels, but do not have acidaemia, bicarbonaturia, aminoaciduria, or phosphaturia. May be acquired or congenital.
Normal serum bicarbonate and arterial pH, normal serum phosphate, and normal measurements of urinary bicarbonate, phosphate, and amino acid excretion.
Primary aminoacidurias
May be confused with Fanconi's syndrome. Patients with primary aminoacidurias demonstrate urinary excretion of one or more amino acids, but do not have acidaemia, glycosuria, or phosphaturia.
Serum bicarbonate, urinary glucose, urinary phosphate excretion, serum phosphate, urine bicarbonate concentration are normal.

Respiratory failure

Hyperventilation secondary to metabolic acidosis
People suffering diabetic ketoacidosis and acidosis from other causes (e.g., aspirin toxicity) have laboured (Kussmaul) breathing.
Arterial blood gas analysis shows metabolic acidosis (low pH, low bicarbonate) and hyperventilation (decreased PaCO2). Pulse oximetry shows normal oxygen saturation.
Hyperventilation secondary to anxiety
People with acute panic attack and other forms of anxiety often present with marked respiratory distress characterised by 'air hunger' or a feeling of dyspnoea.
Arterial blood gas analysis shows respiratory alkalosis with an elevated pH and decreased PaCO2. Pulse oximetry shows normal oxygen saturation.
Sleep apnoea
People with marked sleep apnoea may present with hypoventilation and prolonged apnoeic spells while sleeping.
During apnoeic spells, arterial blood gas analysis may show decreased PaO2 and elevated PaCO2 and pulse oximetry shows hypoxia. When awake and stimulated by daily routines, arterial blood gases are often normal. Sleep apnoea is diagnosed by a formal sleep study.
Obesity
People with marked obesity may present with hypoventilation and prolonged apnoeic spells while sleeping.
During apnoeic spells, arterial blood gas analysis may show decreased PaO2 and elevated PaCO2 and pulse oximetry shows hypoxia. When awake and stimulated by daily routines, arterial blood gases are often normal.

Respiratory syncytial virus infection

Human metapneumovirus
Produces a clinical syndrome that closely mimics respiratory syncytial virus (RSV). May be indistinguishable by clinical findings. [66]
Viral cultures and polymerase chain reaction (PCR) have been developed but are not yet widely available.
Influenza virus
Accounts for 1% to 24% of bronchiolitis. [65] [67] [68] Closely mimics RSV in presentation. Fever frequently >38.9°C (>101.9°F). Coryza frequently present. Greater frequency of pneumonia than with RSV.
Chest x-ray (CXR) may show infiltrates.Rapid testing by immunoassay or viral neuraminidase detection: positive for influenza virus.Enzyme-linked immunosorbent assay (ELISA): positive for influenza virus.
Parainfluenza virus
Accounts for 10% to 30% of bronchiolitis. Parainfluenza type 3 closely mimics RSV in presentation. Presence of coryza is associated with parainfluenza infection.
ELISA and PCR testing: positive for parainfluenza virus.Viral culture: positive for parainfluenza virus (standard test).
Bacterial pneumonia
Bacterial infections are not associated with wheeze and generally cause higher fevers than RSV. [57]Fever >40°C (>103.9°F).
CXR: infiltrateWhite blood cell count: elevated with left shift suggests an active bacterial process.

Restless legs syndrome

Periodic limb movement disorder (PLMD)
Unlike in RLS, there is no urge to move the limbs for comfort, and moving limbs does not offer comfort.Evaluation for RLS on polysomnographic overnight studies often reveals PLMD, but patients with PLMD may not necessarily have RLS.
RLS can be diagnosed clinically, while the criteria for PLMD by polysomnographic overnight sleep study are EMG burst length (0.5 to 5.0 seconds), period (4 to 90 seconds), and minimal train length (4 movements).
Akathisia
The desire to move often comes from mental or central discomfort or restlessness, not from uncomfortable sensations in the extremities. Symptoms do not tend to follow a circadian rhythm.
No differentiating tests.
Peripheral neuropathy
Peripheral neuropathy has other symptoms not typically associated with RLS, such as numbness, paraesthesias, dysaesthesias, and impaired balance or gait.
EMG and nerve conduction studies are normal in RLS. [1]
Nocturnal leg cramps
Associated with muscle hardening, which is usually not present in RLS.
No differentiating tests.

Retinal detachment

Retinoschisis
Degenerative (peripheral) retinoschisis and rhegmatogenous RD can coexist in the same eye. However, retinoschisis is commonly bilateral and rather symmetric.
Indirect ophthalmoscopy with sclera indentation and slit-lamp biomicroscopy show that the fluid is intraretinal, rather than sub-retinal, and therefore does not shift with scleral depression. There is no pigment in the vitreous cavity; the retinal surface has a 'beaten-metal' appearance. [31]
Diabetic retinopathy
Disease is usually symmetric between the eyes.Examination shows microaneurysms, haemorrhages, and neovascularisation on both sides of the horizontal raphe in the absence of collateral vessels. Vitreous haemorrhage is a common complication; this does not differ in its presentation from that seen in conjunction with a retinal detachment.
Clinical diagnosis.Fluorescein angiogram shows multifocal areas of non-perfusion.Ultrasonography may help identify the presence of a retinal break and absence of a retinal detachment.
Retinal vein occlusion
Clinical presentation may be similar (vitreous haemorrhage, sudden loss of vision).
Clinical diagnosis.Fluorescein angiogram shows focal or multifocal areas of non-perfusion.Ultrasonography may help identify the absence of a retinal detachment.

Retinal vein occlusion

Ischaemic optic neuropathy
Ischaemic optic neuropathy is infrequently associated with intra-retinal haemorrhages and retinal thickening.
Clinical diagnosis; no differentiating tests.
Retinal detachment (RD)
Patients usually report photopsias and/or floaters.Examination demonstrates an RD.
Clinical diagnosis; no differentiating tests.
Choroidal neovascularisation (CNV)
Examination demonstrates sub-retinal or sub-retinal pigment epithelium haemorrhage in addition to signs of diseases associated with CNV (e.g., age-related macular degeneration, pathological myopia, ocular histoplasmosis).Intra-retinal and vitreous haemorrhages are infrequently related to CNV.
Clinical diagnosis; no differentiating tests.
Central retinal artery occlusion
Venous pathology, intra-retinal haemorrhages, and macular oedema infrequently seen on examination.Affected retina is whitened.Cilioretinal artery sparing and/or foveal sparing may be seen.
Clinical diagnosis; no differentiating tests.
Branch retinal artery occlusion
Venous pathology, intra-retinal haemorrhages, and macular oedema infrequently seen on examination.Affected region of retina is whitened.
Clinical diagnosis; no differentiating tests.
Ophthalmic artery occlusion
Venous pathology, intra-retinal haemorrhages, and macular oedema infrequently seen on examination.Entire retina is whitened.
Clinical diagnosis; no differentiating tests.
Cerebral vascular accident
Infrequently associated with any posterior segment findings.Usually associated with other neurological signs (e.g., extremity numbness or weakness, slurred speech, confusion).
Clinical diagnosis; no differentiating tests.
Optic neuritis
Frequently associated with pain and infrequently associated with retinal haemorrhages and thickening that are restricted to a single quadrant.
Clinical diagnosis; no differentiating tests.
Diabetic retinopathy
Examination demonstrates micro-aneurysms, haemorrhages, and neovascularisation that occur on both sides of the horizontal raphe in the absence of collateral vessels.Cotton-wool spots and nerve fibre layer haemorrhages are less frequent in diabetic retinopathy than in RVO.
Fluorescein angiogram less likely to show leakage from the optic nerve head. Areas of non-perfusion are multi-focal and not limited to a single quadrant as in RVO.
Ocular ischaemic syndrome
Carotid occlusive disease may be present in patient's medical history. Retinal haemorrhages and neovascularisation tend to be in the mid-periphery.Ocular ischaemic syndrome usually either unilateral or, at least, significantly asymmetrical.
Fluorescein angiogram demonstrates delayed choroidal filling. Delayed venous filling, if present, is not limited to a single quadrant.
Radiation retinopathy
History of radiotherapy to head, orbits, or globes.Examination demonstrates micro-aneurysms, haemorrhages, and neovascularisation that occur on both sides of the horizontal raphe in the absence of collateral vessels.
Fluorescein angiogram does not demonstrate delayed venous filling.
Sickle cell retinopathy
History of sickle cell or sickle thalassaemia disease.Areas of neovascularisation tend to be peripheral, 'sea-fan' shaped, and self-limited.
Fluorescein angiogram does not demonstrate delayed venous filling.
Hypertensive retinopathy
Attenuated arterioles, arteriovenous crossing changes seen throughout the fundus, but not necessarily associated with increased venous tortuosity, dilation, and retinal thickening.
Fluorescein angiogram does not demonstrate delayed venous filling.

Retinitis pigmentosa

Congenital rubella
Granular pigmentary changes on funduscopy. These tend to be more granular than the bone spicules seen in RP, but funduscopy alone cannot reliably distinguish the difference. Congenital deafness may also be present. Other features include microcephaly, mental retardation, microphthalmia, and congenital cataracts.
Normal electroretinogram (ERG).Positive blood test for rubella antibodies confirms infection.
Syphilis
Pigmentary changes, evidence of retinal vasculitis (such as sheathed vessels), and placoid (plate-like) areas of chorioretinal inflammation. Other features include a firm painless chancre at the site of infection, skin rash, and general symptoms of fatigue, weight loss, and lymphadenopathy.In congenital syphilis there may be a rash, swollen liver, anaemia or jaundice, and rhinitis.
Serum Venereal Disease Research Laboratory test (VDRL) will be positive.Serum rapid plasma regain test (RPR) will be positive.
Vitamin A deficiency
Presents with night blindness and malnutrition. Particularly seen in pregnant women in developing countries.
Reversibility of night blindness with high-dose vitamin A (retinol) supplementation.
Ophthalmic artery occlusion
Sudden-onset, severe, unilateral but painless loss of vision. May have hx of amaurosis fugax.
Fundus angiography showing impaired choroidal perfusion.Carotid Doppler scans demonstrating high-risk plaques.
Posterior uveitis
A greater degree of inflammation and signs of chronic inflammation such as posterior synechia, choroidal infiltrates in active phase, asymmetrical changes, and presence of vascular cuffing indicating vasculitis.
Elevated WBC/CRP and ESR, non-specific markers of inflammation.Further tests depend on likely underlying cause: Lyme titer (can cause uveitis in endemic areas); PPD test (positive for patients with suspected tuberculosis); antinuclear cytoplasmic antibodies positive in 90% of patients with Wegener granulomatosis).
Retinal detachment
May have hx of risk factors, including ocular trauma, previous detachment, or cataract surgery. Hx of sudden-onset central visual loss, possibly with preceding flashes of light. On examination there is subretinal fluid and cystic degeneration in an asymmetrical pattern.
Slit lamp examination and indirect ophthalmoscopy: retinal detachment; retinal break; vitreoretinal pathology (traction or presence of pigment).
Diffuse unilateral subacute neuroretinitis
Usually a unilateral condition; patient may report floaters or conjunctivitis in the early stages with mild visual loss. More severe visual loss and central scotomas may be evident in later disease. On funduscopic examination crops of yellow creamy-appearing choroidal infiltrates can be seen in the active phase, caused by a nematode worm. Late changes are indistinguishable from RP.
Funduscopic examination is usually sufficient.Scanning laser ophthalmoscope: an infrared laser that is good for identifying live worms in young patients.
Autoimmune retinopathy
Symptoms depend on whether rods or cones are predominantly affected and are clinically indistinguishable from RP. On funduscopic examination there is retinal vascular atrophy but without pigmentary changes.
Positive serum antiretinal antibodies.
Congenital stationary night blindness
Relatively normal-appearing fundus; night blindness is non-progressive. Nystagmus is frequently a feature.
Decreased b- to a-wave ratio on ERG.Genetic testing confirms diagnosis.
Fundus albipunctatus
Also presents with symptoms of night blindness but on examination there are small white spots on the retina.
Elevated final dark-adapted threshold: impaired dark adaptation that recovers with prolonged time in the dark.Genetic testing confirms diagnosis.
Achromatopsia
Typically diagnosed at about 6 months of age. Decreased visual acuity with photophobia and complete colour blindness. Nystagmus becomes less noticeable with age.
Severely diminished photopic ERG but normal scotopic ERG.Genetic testing confirms diagnosis.
X-linked retinoschisis
Variable hx can be mild gradual loss of central vision or sudden severe visual loss with a vitreous haemorrhage. Foveoschisis (splitting of the retinal layers) can appear similar to cystoid macular oedema on funduscopy. Peripheral retinal schisis may also be seen.
Decreased b- to a-wave ratio on ERG.
Choroideraemia
X-linked disorder, so usually only males are affected. Extensive chorioretinal atrophy with sparing of the macula until late stages. Normal-appearing retinal vessels and optic nerve.
Genetic testing.
Gyrate atrophy
Total blindness usually occurring in middle age (40-60 years).Peripheral areas of chorioretinal degeneration in gyrate patterns.
Elevated blood ornithine levels.Genetic testing confirms diagnosis.

Retropharyngeal abscess

Acute epiglottitis
Difficult to distinguish from RPA but generally has a more acute onset.Hx of difficulty in breathing.
CT scan would not show a ring-enhancing lesion in retropharyngeal space.Lateral soft tissue neck x-ray shows radio-opaque shadow of inflamed epiglottis.
Laryngotracheobronchitis
Barking cough.
CT scan would not show a ring-enhancing lesion in retropharyngeal space and would show clinically normal appearance of oropharynx.
Meningitis
Headache; purpuric rash may also be present in some cases.
CT scan would not show a ring-enhancing lesion in retropharyngeal space.Positive finding on lumbar puncture.
Tonsillitis
Clinical examination confirms presence of infected tonsils with normal appearance of posterior pharyngeal wall.
Diagnosis is clinical.
Peritonsillar abscess
Peritonsillar swelling and medialised uvula.Normal appearance of the posterior pharyngeal wall on clinical examination.
Aspiration or incision and drainage of the swelling confirms diagnosis.
Retropharyngeal lymphadenopathy
Non-fluctuant swelling of posterior pharyngeal wall.
CT scan with contrast differentiates between lymphadenopathy and abscess.
Nasopharyngeal carcinoma
Persistent lymphadenitis.Non-resolving symptoms despite adequate treatment.
Biopsy and cytology confirms presence of neoplasia.
Epstein-Barr virus infection
Hepatosplenomegaly and generalised lymphadenopathy may be present.
Paul-Bunnell or monospot tests are positive.
Retropharyngeal calcific tendonitis
Signs and symptoms are very similar to RPA.It is self-limiting and usually settles after 2 weeks.
CT scan shows calcification anterior to the C1 and/or C2 vertebral body(s) with a non-ring-enhancing fluid collection in the prevertebral space. [17]
Kawasaki disease (KD)
May have features of RPA, but lymphadenopathy is rarely seen in isolation or as the initial presentation.Diagnostic features of KD include >5 days of pyrexia with 4 of 5 clinical criteria: nonpurulent bulbar conjunctivitis, changes in the lips or oral cavity, polymorphous exanthem, erythema with later desquamation of the extremities, and at least one cervical lymph node >1.5 cm in size.
CT scan shows features that are very similar to retropharyngeal abscess, so the clinician must rely on the clinical features. [18]

Reye's syndrome

Head injury
No specific clinical differentiating features.Hx of head injury is frequently obtained, but can be unavailable in someone who is found unresponsive.
CT and MRI will reveal various intracranial bleeds that are associated with head injury; concussions have normal imaging findings; diffuse axonal damage can be seen as signal abnormality in MRI images.
Acute bacterial meningitis
Persistent irritability and lethargy, prolonged postictal obtunded consciousness, skin rash, bulging fontanel, and nuchal rigidity.
Typical CSF abnormalities are pleocytosis, elevated protein, low glucose level, and positive culture.
Viral meningitis
Fever, headache, and neck stiffness are common. Nausea, vomiting, and photophobia can also occur.
CSF lymphocytic pleocytosis.Glucose is normal or high.Gram stain and bacterial culture are negative; viral culture and PCR may be positive.
Viral encephalitis
Prodromal upper respiratory symptoms with fever and malaise, followed by headache, stiff neck, and seizure.Skin rash also common.
LP may show pleocytosis and increased protein but is sometimes normal.Culture is negative for bacteria.Results of viral studies are positive (i.e., HSV, varicella).
Ingestion of toxic substances
Hx of ingestion of ethanol, methanol, ethylene glycol (constituent of automobile antifreeze), or propylene glycol (diluent in many intravenous medications such as lorazepam) is present.
Serum toxicology screen will identify the ingested substance.
Paracetamol overdose
Hx of chronic paracetamol ingestion or paracetamol overdose is present.Clinical signs include confusion, tinnitus, hyperventilation, and pulmonary oedema.
Urine and serum paracetamol levels will be positive, but not necessarily in the toxic range.
Salicylate poisoning
Hx of chronic salicylate ingestion or salicylate overdose is present.
Serum salicylate levels will be elevated.
Diabetic ketoacidosis
Patients usually have a hx of preexisting diabetes.May present with polyuria and polydipsia.
Plasma glucose 13.9 mmol/L (>250 mg/dL).Venous pH <7.3.HCO3 <15 mmol/L; anion gap >12.Presence of serum ketones or betahydroxybutyrate.
Urea cycle disorders
Hx or FHx of metabolic defect.Typically present with recurrent hypoglycaemia.
Enzyme assay or mutation analysis will be positive for a urea cycle disorder.
Type 1 glycogen storage disease
Hx or FHx of metabolic defect.Typically present with recurrent hypoglycaemia.May show evidence of growth retardation, with hepatomegaly and protuberant abdomen.
Mutation analysis will be positive for GSD I mutations.
Primary carnitine deficiency
Hx or FHx of metabolic defect.Typically present with recurrent hypoglycaemia.
Enzyme assay will be positive for a carnitine deficiency.
Fatty acid oxidation disorders
Hx or FHx of metabolic defect.Hx or FHx of recurrent hypoglycaemic episodes.Frequently presents with lethargy/coma, hepatosplenomegaly. May also present with vomiting, feeding difficulties, cardiomegaly, developmental delay, seizures, ataxia. [13]
Plasma and urine analysis of carnitine and acyl-carnitine levels reveals disorder.Additional plasma and fibroblast studies ordered through genetics consultation.

Rhabdomyolysis

Myocardial infarction
Presence of typical history of substernal chest pain with associated risk factors, signs, and symptoms.
ECG may have ST segment changes that suggest infarction.Serum CK can be found as MM (muscle), MB (cardiac), and BB (brain) iso-enzymes.CK-MB greater than 5% of total CK levels suggests a cardiac source.
Influenza
Myalgia, accompanied by respiratory tract symptoms, fever, and headache.
CK not elevated unless influenza viral myositis is present. This is very rare and is more likely in children.Culture, serology, or antigen detection immunoassays may be used, but are not sensitive or specific and need to be interpreted with the clinical findings.
Fibromyalgia
Widespread body pain with areas of focal tenderness at designated points.Diagnosis made on clinical criteria.
CK not elevated.

Rhabdomyosarcoma tumor High risk group

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Rhabdomyosarcoma tumor Intermediate Risk Group

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Rhabdomyosarcoma tumor Standard and Low risk group

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Rheumatic fever

Septic arthritis
Usually only one joint involved; not migratory; patient looks toxic.
Positive gram stain from synovial fluid aspirate.Culture of an organism from aspirate.Elevated white cell count in blood and on microscopy of synovial fluid.May have positive blood culture.
Juvenile arthritis
Lasts longer than 6 weeks; may not have joint pain; eye inflammation may be present. Light pink rash in systemic form.
Positive connective tissue testing such as positive ANA, anti-dsDNA.
Viral arthropathy
History of viral illness.
Positive viral serology.
Reactive arthropathy
Most common in males aged 20 to 40 years, and often accompanied by urethritis and/or conjunctivitis.
No specific test, urethral culture for infection may reveal cause of urethritis.
Lyme disease
Circular expanding rash with central clearing (erythema migrans); influenza-like symptoms; acute neurological problems including Bell's palsy; arthritis usually affects the knees.
Positive Borrelia burgdoferi serology.
Sickle cell anaemia
Family history; signs and symptoms of anaemia; not usually febrile unless infection has precipitated crisis.
Anaemia and sickle cells on blood film.
Infective endocarditis
Janeway lesions, Osler nodes, and splinter haemorrhages.
Positive blood culture for organism causing endocarditis.Echocardiogram; vegetations on valve.
Leukemia
History may include lethargy, weight loss, night sweats, and bone pain.
Blast cells on film.
Gout and pseudogout
First metacarpophalangeal joint often affected, pain excruciating and often flaky red skin over affected joint.
Polarising microscopy of synovial fluid or presence of gouty tophi.
Innocent murmur
Otherwise normal child; quiet murmur; never purely diastolic.
Normal echocardiogram.
Mitral valve prolapse
Mid-systolic click on cardiac auscultation.
Echocardiogram reveals characteristic billowing of one or both of the mitral valve leaflets into the left atrium during/towards the end of systole.
Congenital heart disease
Murmur does not radiate to the apex.
Echocardiography will reveal abnormalities.
Hypertrophic cardiomyopathy
Afebrile, may be asymptomatic.
Echocardiography shows hypertrophy of left ventricle without dilatation of cavity.
Myocarditis
Usually follows a viral illness; chest pain and shortness of breath are common features.
Troponin and CK elevated.ECG may show saddle-shaped ST segments or T-wave changes.Cardiac MRI will demonstrate myocarditic inflammation.Cardiac muscle biopsy will demonstrate cardiac muscle inflammation.
Pericarditis
Pleuritic chest pain, pericardial friction rubs on auscultation.
Echocardiography may show a pericardial effusion.
SLE
Malar 'butterfly' rash; joint pain typically affects hand and wrist; may have anaemia.
Positive connective tissue testing such as positive ANA, anti-dsDNA, and anti-Smith antibodies.
Drug intoxication
History of recent ingestion; use of illicit drugs.
Drug screen, including phenytoin, amitriptyline, and metoclopramide.
Wilson's disease
Hepatosplenomegaly and Kayser-Fleischer rings; may have a family history.
Decreased ceruloplasmin level, genetic testing.24-hour urinary copper excretion.
Tic disorder
Can be motor or phonic tics; absence of fever or any other signs of acute rheumatic fever.
Psychiatric evaluation may reveal underlying cause.
Encephalitis
Seizures, headache, fever, sometimes photophobia and neck stiffness.
EEG may show temporal lobe changes.MRI brain: features depend on cause of encephalitis but may include temporal lobe haemorrhage or white matter lesions.PCR of CSF to detect viral DNA/RNA.
Choreoathetoid cerebral palsy
Wide spectrum of symptoms depending on severity; features include difficulty maintaining posture, scissor walking, seizures, and learning difficulties.
Clinical diagnosis. CT may help to identify cerebral haemorrhage, and MRI can be useful to look for changes in cerebral white matter in older children.
Huntington's chorea
May have associated symptoms of weight loss, depression, facial tics, impairment of rapid eye movement, and dementia. More likely if a parent is affected.
Genetic testing (triplet repeat).
Intracranial tumour
May have headache, typically worse in the morning, with or without vomiting; may have papilloedema; cranial nerve involvement possible.
CT/MRI of the brain.
Hyperthyroidism
Tachycardia, tremor, weight loss.Eye signs: exophthalmia, lid lag and retraction, proptosis.
Thyroid function tests; typically elevated T4 and T3 with suppression of TSH in primary hyperthyroidism. Secondary hyperthyroidism will show elevated TSH levels.

Rheumatoid arthritis

Psoriatic arthritis (PsA)
Commonly involves small joints of the hands and feet but is less often symmetric. Fewer than 5 joints are commonly affected (oligoarthritis). Unlike RA, the distal interphalangeal (DIP) joints may be involved in psoriatic arthritis.Psoriasis is present in >90% of PsA patients and it is unusual in RA patients.
PsA is for the most part seronegative, even though there are patients with low levels of rheumatoid factor (RF) diagnosed with PsA because of presence of psoriasis.Skin biopsy of suspicious lesions can show psoriasis, supporting the diagnosis.
Infectious arthritis
Mostly in the form of reactive arthritis, symmetric hand and feet arthritis can be seen after viral/bacterial infections.
Most resolve within 6 weeks and leave no long-term effects.
Gout
Small percentage of gout patients present with polyarticular gout, and can mimic RA. Tophi and high levels of uric acid are specific for gout and very rare in RA. In addition, erosions seen in gout where the tophi have eroded into the bone are different from the erosions seen in RA.
Serum uric acid >416 micromols/L (>7 mg/dL), urate crystals from the joint aspirate or tophus. Tophus eroding into the joint in gout is more destructive and much larger; RA erosions are more limited to cartilage-bone interface and tend to be smaller.
Systemic lupus erythematosus
SLE can have polyarthritis in the small joints of the hands and feet as a presenting manifestation. The main difference is that SLE arthritis is usually non-deforming.
A wide range of autoantibodies seen in SLE help differentiate the two conditions. High antinuclear antibody (ANA) titre, anti-extractable nuclear antigen (ENA) autoantibodies are seen rarely in RA.On radiographs, erosions are not typically seen in the joints of SLE patients.
Osteoarthritis
Prevalence increases with age. The most commonly affected joints are the knee, hip, hands, and lumbar and cervical spine. Patients present with joint pain and stiffness that is typically worse with activity.
Radiographs show loss of joint space, subchondral sclerosis, and osteophytes.

Rh incompatibility

Non-immune fetal hydrops
Hydrops fetalis consists of generalised subcutaneous oedema and fluid collections in some or all serous cavities.Placental calcification, oligohydramnios, and intrauterine growth restrictions may be associated with congenital infections. [23] [22]
Maternal serum antibodies are negative in non-immune fetal hydrops. There are more than 80 causes of fetal hydrops.Non-immune hydrops carries a high rate of infant mortality, and in many cases (17%) its cause remains indeterminate after diagnostic work-up. [21]
Parvovirus infection
Hx of environmental exposure to parvovirus may arouse suspicion of possible infection in asymptomatic people.Symptoms include maternal fever, myalgia, coryza, headache, nausea, and erythematous, maculopapular exanthema on the trunk and limbs. Arthropathy and arthritis are also common in women and adolescents.Progressive fetal anaemia, due to preferential destruction of immature erythrocytes by the virus, leads to hydrops and intrauterine fetal death. [17] [24]
Viral-specific IgM appears about 10 to 12 days after infection. Fetal infection is confirmed by analysing amniotic fluid, cord blood, or serous fluid for viral DNA or RNA by PCR. [24]When severe fetal anaemia or hydrops is diagnosed, intrauterine fetal transfusion is recommended. In early gestational age (<20 weeks) disease, intraperitoneal transfusion is recommended. [3]
Non-RhD haemolytic disease
Usually transfusion induced. The mechanism for fetal anaemia is haemolysis and erythroid suppression.Prior obstetrical hx does not reliably predict occurrence in subsequent pregnancy, and maternal antibody titre does not correlate with severity. [3]Kell's alloimmunisation is the most common non-RhD haemolytic disease, with an incidence of 0.1% to 0.2% in the obstetric population.
Serum antibodies can be detected in the maternal blood. Although the titre is not as reliable as in RhD disease, severe disease is unusual with titres <1:32, with the exception of anti-Kell's antibodies where significant fetal disease can occur at much lower titres.Middle cerebral artery (MCA) Doppler should be performed and has been shown to be reliable for fetal anaemia detection.Fetal haemoglobin should be assessed by cordocentesis when non-invasive testing (MCA Doppler) is abnormal. [3]
Placental chorioangioma
May be present in up to 1% of pregnancies.Large placental masses of 5 cm or greater may produce complications such as fetal anaemia, hydrops, and polyhydramnios, and poor perinatal outcome. [17]
A solid placental mass is detected by standard 2-dimensional sonography, and colour Doppler sonography reveals a pulsatile mass.Maternal serum alpha-fetoprotein may be high in association with a placental chorioangioma. Doppler velocimetry of the MCA may be consistent with fetal anaemia. [25]
Fetomaternal haemorrhage
Severe, acute fetomaternal haemorrhage may be entirely asymptomatic or manifest as a reduction in perceived fetal movements by the mother. Clinical symptoms are usually non-specific.
Peak systolic velocity on MCA Doppler may be increased.Kleihauer-Betke's test (persistence of fetal RBCs in maternal serum after denaturation by strong acid) or flow cytometry is also helpful. [17]
Twin-twin transfusion syndrome
Develops in association with monochorionic twin placentation, usually between 15 and 26 weeks' gestation. It is found in 5.5% to 17.5% of all monochorionic pregnancies.
Ultrasound findings include polyhydramnios in one twin (recipient), and amniotic sac and oligohydramnios in the other (donor).Growth of fetuses is usually discordant. [26]Hydrops may develop in later stages of the disease, usually in the recipient co-twin.Perinatal mortality may reach 80% to 100% when untreated. [26]

Rib fractures

Chest wall contusion
Clinical signs and symptoms may be similar to a simple rib fracture.
Absence of rib fracture on CXR or chest CT.

Rickets

Hypophosphatasia
An autosomal recessive disorder that radiographically resembles rickets.This is an inborn error of metabolism in which activity of the tissue-non-specific (liver/bone/kidney) alkaline phosphatase is deficient. [5]
Defined by low serum alkaline phosphatase activity.Large quantities of phosphoethanolamine are found in the urine.
Metaphyseal dysostoses
Includes Jansen and Schmid types of metaphyseal dysostosis and Pyle's disease.Bowing of the legs, short stature, and a waddling gait. [5]
Absence of abnormalities of low serum levels of calcium and phosphate, alkaline phosphatase activity, or vitamin D metabolites.
Blount's syndrome
Condition that causes osteochondrosis of the tibia, resulting in bowing of the legs. May be related to obesity.
Absence of abnormalities of low serum levels of calcium and phosphate, alkaline phosphatase activity, or vitamin D metabolites.
Benign hyperphosphatasia
A benign condition of elevations of serum alkaline phosphatase levels. May be transient or permanent.
Absence of radiological findings of rickets.
Chronic renal failure
Chronic renal failure can cause a rickets-like clinical picture, but this is rarely a presenting finding.
Abnormal renal function tests.

Rocky Mountain spotted fever

Meningococcaemia
More prevalent in winter and early spring. Rash characteristically begins earlier than in Rocky Mountain spotted fever (RMSF), starting centrally and spreading peripherally. [7] Septic shock, disseminated intravascular coagulation, and digital necrosis more likely than in RMSF.Rarely, other pyogenic bacteria, such as Streptococcus pneumoniae or Staphylococcus aureus, can produce bloodstream infections with similar signs to meningococcaemia.
Blood cultures (and sometimes CSF cultures) positive for Neisseria meningitidis.
Human monocytic ehrlichiosis
Less frequent rash (present in one third of adults, two-thirds of children).
More frequent leukopenia (60%), thrombocytopenia (90%), and aminotransferase elevations (70% to 90%). [15] Intracellular morulae may be visible in cytoplasm of monocytes. [7]Diagnosed by positive PCR, rising serum antibody titres, or isolation in culture of Ehrlichia chaffeensis. [7]
Human granulocytic anaplasmosis (formerly human granulocytic ehrlichiosis)
Rash is rare.
Intracellular morulae may be visible in cytoplasm of neutrophils. [7]Diagnosed by positive PCR or rising serum antibody titres against Anaplasma phagocytophila. [7]
Toxic shock syndrome (TSS)
Presents with macular erythroderma that subsequently desquamates. [7] Clinical criteria for TSS also include fever, low BP, and abnormalities in three or more other organ systems.
Fifty percent or greater of Group A beta haemolytic streptococcal TSS will have the organism isolated from a normally sterile site.
Scarlet fever
Pharyngitis more pronounced than in RMSF.
Throat culture or antigen detection test positive for Streptococcus pyogenes.
Leptospirosis
Typically follows biphasic course; rash is only petechial in the second phase.
Serological diagnosis with microagglutination assay for leptospirosis.
Viral exanthems
Rash rarely involves palms or soles in viral illnesses. [7] Rapidly improving clinical course without antirickettsial therapy suggests a viral illness.
Viral exanthems are usually diagnosed clinically. Sometimes confirmed with viral cultures or serology.

Roseola

Measles
Typically accompanied by a prodrome of cough, coryza and conjunctivitis and an enanthem consisting of grey-white papules on the buccal mucosa (Koplik spots).The exanthem is an erythematous maculopapular eruption that spreads cephalocaudally and usually begins to clear within 1 week. [11]
Diagnosis is usually clinical, based on physical examination and history.Virus isolation can be obtained from a nasopharyngeal swab using a serological assay for measles-specific antibodies. [11]
Enterovirus
The exanthem associated with enterovirus (especially echovirus) is a non-specific, maculopapular, erythematous eruption.Enterovirus often presents as aseptic meningitis.Other enteroviruses may present with herpangina or vesicular lesions.Primary differentiation is made based on history, but can be difficult. [12]
PCR or rising serological titres may be used for enterovirus identification in serious cases.In many uncomplicated cases, history and physical examination are sufficient. [12]
EBV
The exanthem is a non-specific, maculopapular, erythematous eruption.The primary differentiation is made based on history.The eruption of EBV often presents after administration of ampicillin or other antibiotic therapy. [13]
Acute EBV is usually diagnosed with a positive heterophile test (Monospot).Atypical lymphocytes are common on examination of a peripheral smear.EBV-specific antibodies are used in patients with a negative Monospot or in cases with atypical symptoms. [13]
Rubella
Presents with a non-specific exanthem of rose-pink macules that spread cephalocaudally.Joint involvement is common, as is tender cervical, occipital and/or posterior auricular lymphadenopathy. [11]
Serology will detect antirubella IgM or a 4-fold increase in antirubella IgG antibodies. [11]
Meningococcaemia
Seizures, fever and signs of encephalopathy can mimic meningococcaemia.Usually associated with a rapidly progressing purpuric eruption and meningeal signs.
Cultures of CSF and blood yield meningococcus.

Rotator cuff injury

Rotator cuff impingement
May have weakness due to pain.
Advanced imaging will not show rotator cuff tear; may show inflammation within tendons or bursa. MRI would also show some increased fluid in the subacromial space and the subdeltoid bursa, as well as increased signal.If the rotator cuff is intact, strength should improve after pain-relieving injection of anaesthetic.
Rotator cuff tendonitis
May have weakness due to pain.
Advanced imaging will not show rotator cuff tear; may show inflammation within tendons.If the rotator cuff is intact, strength should improve after pain-relieving injection of anaesthetic.
Subacromial bursitis
May have weakness due to pain.
Advanced imaging will not show rotator cuff tear; may show inflammation within bursa.If the rotator cuff is intact, strength should improve after pain-relieving injection of anaesthetic.View image
Greater tuberosity humerus fracture
Identical presentation to acute tear.
X-ray findings of fracture.
Biceps tendonitis
Tenderness at bicipital groove.
Advanced imaging reveals inflammation surrounding biceps tendon and occasionally intrasubstance signal change.Pain in the anterior region of the shoulder with Speed test (resisted forward arm flexion with the elbow extended) or Yergason test (resisted forward supination).
Glenohumeral osteoarthritis
Can co-exist with an acute rotator cuff tear, but the symptoms for each diagnosis differ. Osteoarthritis results in painful glenohumeral stiffness and limitation of active and passive motion. In contrast, loss of passive motion in rotator cuff tear is uncommon. Degenerative changes can occur following untreated chronic massive rotator cuff, but such changes are relatively uncommon immediately following an acute tear.
X-rays demonstrate typical changes of osteoarthritis (decreased joint space, subchondral sclerosis, subchondral cysts, and osteophyte formation).
Superior labral tear
Weakness is not a presenting symptom.
MRI finding of a superior labral tear.Pain during active compression test (resisted arm elevation with the arm 15° adducted, forward flexed parallel with the floor and maximal pronation).
Acromioclavicular arthritis
Pain over superior aspect of shoulder, especially at acromioclavicular joint.Overhead and cross-body activities exacerbate pain.
X-rays and MRI demonstrate arthritic changes or inflammation at the acromioclavicular joint.Pain localised to the acromioclavicular joint during cross-body test (the patient's shoulder is forward flexed to 90° and adducted across body).

Rotor's syndrome

Dubin-Johnson syndrome
Clinically similar, no differentiating symptoms or signs.
Liver pigmentation present. In Rotor's syndrome (RS), the liver has a normal appearance.Failure to visualise the gall bladder on oral cholecystography. [4]Total urinary coproporphyrin excretion is either normal or moderately increased, but >80% is excreted as coproporphyrin I. [4] [8] In RS, the proportion is much lower at approximately 65%.
Gilbert's syndrome
Most common in males. [13]
Presence of unconjugated hyperbilirubinaemia in serum and urine. [13]
Crigler-Najjar syndrome (type I and II)
Diagnosed usually during the neonatal period.More intense jaundice.
Presence of unconjugated hyperbilirubinaemia in serum and urine. [13]
Extra-hepatic biliary obstruction
Pruritus.Acholic stools.
Elevated alkaline phosphatase.Elevated gamma-GT.
Familial intra-hepatic cholestasis
Pruritus.Age usually <1 year.
Elevated bile acids.Abnormal LFTs.
Benign recurrent intra-hepatic cholestasis (BRIC)
Recurrent attacks of cholestasis lasting several days to months.Each episode preceded by intense pruritus and malaise, lassitude, and sometimes diarrhoea.Pale stools during the episode.Weight loss due to steatorrhoea.
LFTs during an episode reflect cholestasis with elevated serum bile acids and alkaline phosphatase.Biopsy specimens during an attack show bile plugs within the ducts.Between attacks liver histology is normal apart from mild portal zone fibrosis. [16]
Drug-induced hepatotoxicity
History of exposure to a known hepatotoxic agent or drug causing cholestasis (e.g., isoniazid, halothane, alpha-methyl dopa, erythromycin, chlorpromazine, oestrogens/oral contraceptives, ciclosporin, haloperidol).
Abnormal LFTs.

Rubella

Measles (rubeola)
Measles is a more severe illness. Erythematous or brownish morbilliform rash spreads from the head and neck downwards and persists for 3 to 7 days. Coryza, cough, and conjunctivitis are usual.A pathognomonic enanthem (Koplik's spots) occurs early in the disease. View imageView image Complications are common, particularly in immunocompromised and malnourished people.
Positive serum measles anti-IgM antibody is the preferred test (sensitivity 83% to 89%, specificity 87% to 100%). [18] [19]Significant rise in serum measles anti-IgG antibody in paired acute and convalescent specimens.Isolation of measles virus from throat, nasopharynx, blood, or urine (usually processed by public health and reference laboratories only).
Roseola infantum (HHV-6, HHV-7, exanthem subitum, sixth disease)
Typically affects children <2 years of age. [20] Coryza, conjunctivitis, and cervical or occipital lymphadenopathy may precede 3 to 7 days of high fever and irritability. Development of an erythematous or pinkish maculopapular rash coincides with the resolution of fever and persists for hours to several days. Febrile seizures occur in 10% to 15%.
Anti-IgG antibody seroconversion between paired acute and convalescent specimens is the preferred test. [21] Increases in serum-specific antibody occur with viral reactivation. Specific serum IgM testing is not reliable. HHV-6 and HHV-7 are serologically cross-reactive.Positive HHV-6/HHV-7 nucleic acid amplification from serum or plasma (sensitivity 90% to 100%, specificity 100%). Cannot distinguish acute infection from reactivation. [22]Isolation of virus from peripheral blood (usually processed by public health and reference laboratories only).
Scarlet fever (group A Streptococcus pyogenes)
Most common in school-age children. Usually associated with streptococcal pharyngitis, but occasionally complicates skin and soft-tissue infection.Pharyngitis, anterior cervical adenopathy, and fever precede a confluent erythematous blanching 'sandpaper' rash that begins on the trunk and behind the ears and is accentuated in flexural creases. Rash resolves with desquamation in 3 to 8 days.Other features include an erythematous-coated 'strawberry' tongue, circumoral pallor, and Pastia's lines (linear erythematous lesions in skinfolds, particularly elbows and axillae). View image
Group A streptococcal rapid antigen testing is 60% to 85% sensitive and 90% to 100% specific. [23] Negative results should be confirmed by throat culture.Isolation of group A streptococcus from throat culture on blood agar is 80% to 98% sensitive and 100% specific.
Erythema infectiosum (parvovirus B19, fifth disease)
Most common in children. Mild systemic symptoms and/or fever are followed in 7 to 10 days by a distinctive erythematous facial rash with a 'slapped cheek' appearance.An erythematous lacy maculopapular rash may also appear on the trunk and spread peripherally to the arms and thighs. Occasionally the rash may be atypical and indistinguishable from that of rubella. Arthralgias and arthritis are more common with increasing age. View image
Positive serum antiparvovirus B19 IgM is the preferred test in immunocompetent people (90% sensitive, 99% specific). [24]Nucleic acid amplification of parvovirus B19 DNA from serum or plasma is more sensitive, but may remain positive for up to 9 months after acute infection. [25]
Enteroviral infections (echovirus, coxsackievirus)
Incidence is highest in infants and young children and in the summer and early autumn. Most common presentation is a non-specific febrile illness. Neurological and GI symptoms and stomatitis may be prominent.
Nucleic acid amplification of enteroviral RNA from blood or CSF is the most rapid and sensitive test. [26]Isolation of enterovirus from stool, rectal swabs, throat, blood, CSF, or urine.Sensitivity and specificity vary, depending on the type of virus, site of infection, and time at which specimens are obtained.
West Nile virus
Incidence highest in summer, coinciding with mosquito activity. Fever is generally higher than that observed with rubella, and headache, myalgias, and weakness are more prominent.A diffuse erythematous maculopapular or morbilliform rash, which spares the palms and soles, is more common in children than adults. Neuro-invasive disease occurs in 0.3% to 1.0% of patients.
Specific IgM by antibody capture ELISA is >95% sensitive and 83% to 99% specific after the first week of illness, but may persist for >1 year. [27]Fourfold increase in virus-specific serum antibody titres. Cross-reactivity with other arboviruses may occur. Positive results should be confirmed by virus-specific IgG.Isolation of virus from CSF or serum.Virus-specific IgM in CSF or amplification of viral nucleic acid from CSF (neuro-invasive disease).
Secondary syphilis
A generalised polymorphous maculopapular rash begins on the trunk and typically involves the palms and soles. Other common manifestations include condyloma lata, mucosal lesions, and generalised lymphadenopathy.Fever and other constitutional symptoms are not prominent. Clinical manifestations resolve spontaneously or with treatment over several weeks to months. View image
Positive VDRL, RPR tests are 100% sensitive and 93% to 99% specific. [28]Results should be confirmed by a specific treponemal test (FTA-ABS, 100% sensitive and 94% to 100% specific).Identification of spirochaetes by dark-field examination of scrapings from moist mucocutaneous lesions.
Infectious mononucleosis (Epstein-Barr virus)
High fever, exudative pharyngitis, cervical or generalised lymphadenopathy, hepatosplenomegaly, and an atypical lymphocytosis are common in adolescents and adults.Periorbital oedema is frequently observed early in infection. Children are more likely to be asymptomatic or have a mild form of illness. A polymorphous rash, usually on the trunk and arms, occurs in up to 20% of cases. Rash is more common in patients treated with ampicillin and other penicillins. Sometimes conjunctival haemorrhage may be seen. View imageView image
Positive antiviral capsid antigen (VCA) IgM antibodies are detectable in the second week of illness and disappear over several months. Anti-VCA IgG antibody is also detectable early in infection and persists for life, whereas anti-EBV-associated nuclear antigen (EBNA) antibody develops weeks to months after infection. The presence of anti-VCA Ab and absence of anti-EBNA Ab are diagnostic of acute infection (sensitivity 95% to 100%, specificity 86% to 100%). [29]Heterophile antibody testing (monospot) is sensitive (81% to 95%) and specific (98% to 100%) in school-age children and adults, but is insensitive in young children.
Kawasaki's syndrome
Occurs almost exclusively in children <8 years of age. Prominent features are a persistent high fever, bulbar conjunctivitis, erythematous changes of the mouth and pharynx, and dry, cracked lips, swelling and pain of the hands and feet, and cervical lymphadenopathy.Irritability, abdominal pain, diarrhoea, and vomiting are common. Peri-ungual desquamation may be noted in the second week of the illness. Coronary and other arterial aneurysms may develop 1 to 4 weeks after the onset of illness.
No specific diagnostic test is available.Suggestive laboratory and diagnostic imaging findings include sterile pyuria, hepatitis, CSF pleocytosis, pericardial effusion, gall bladder hydrops, and coronary artery abnormalities.
Cutaneous drug reactions
Medications commonly associated with cutaneous reactions include antibiotics and anticonvulsants. Many drug-induced rashes have characteristic features (erythema multiforme, urticaria). View image
Clinical diagnosis based on exposure history, resolution after withdrawal of the implicated drug, and exclusion of other potential causes. Eosinophilia is suggestive, but not diagnostic, of cutaneous drug reactions.
Juvenile rheumatoid arthritis
Systemic-onset juvenile rheumatoid arthritis commonly affects children and adolescents. Children are often ill-looking. Typically there are daily high-spiking fevers that, in the absence of therapy, persist for weeks to months.The rash is evanescent, salmon-coloured, and linear and typically involves the trunk and extremities. The presence of the rash often coincides with fever. Mild hepatosplenomegaly and myalgias (or muscle tenderness) are common. Serositis may occur.Many patients develop a chronic synovitis of ≥1 joints, but the onset of joint involvement may be delayed.
There is no definitive laboratory test. Leukocytosis, thrombocytosis, anaemia, elevated ESR, and elevated serum ferritin concentrations are suggestive.

Salicylate poisoning

Diabetic ketoacidosis
Hx of diabetes associated with sub-optimal insulin therapy. Recent or current acute medical illness may be the precipitating factor.Common symptoms include abdominal pain associated with polyuria, polyphagia, and polydipsia.
Blood glucose >13.9 mmol/L (>250 mg/dL) with presence of acidosis and ketonaemia.
Dementia
More common among the older population. May be FHx of Alzheimer's dementia or personal hx of cerebrovascular accident.Cognitive decline usually more gradual.
Head CT or MRI scan shows hippocampal volume loss in cases of Alzheimer's, vascular, and Lewy body dementia; slowing of background rhythm on EEG is common finding of Alzheimer's and Lewy body dementia.
Paracetamol overdose
Hx of repeated non-prescription analgesic use for pain relief may be present.Acute paracetamol overdose produces few clinically useful findings on physical examination, particularly during the first 12 hours.Poisoning may cause various degrees of liver injury, including fulminant hepatic failure and hepatorenal syndrome. Initial coma and severe metabolic acidosis are rare.
Serum paracetamol concentration may be positive.
Toxic alcohol ingestion (ethanol, ethylene glycol, methanol, or isopropyl alcohol)
Hx of chronic alcohol consumption may suggest ethanol toxicity. Hepatomegaly and signs of chronic liver disease may be present (spider nevi, leukonychia, palmar erythema, bruising, jaundice, scratch marks).Hx of automobile anti-freeze or brake fluid ingestion in a confused patient with signs of metabolic acidosis (e.g., Kussmaul's respirations) suggests ethylene glycol poisoning.Methanol toxicity is suggested by blindness or diminished visual acuity and optic neuritis on funduscopic examination. In addition, seizures can occur and signs of metabolic acidosis may be present (e.g., Kussmaul's respirations).Gait disturbances, dizziness, and confusion are common features of isopropyl alcohol ingestion. Hypothermia and hypotension may result from ingestion of large doses. [16]
Serum toxicology screen (ethanol, methanol, ethylene glycol, isopropyl alcohol): positive; presence of osmolar gap, and an anion gap; [17] elevated serum lactate.
Lactic acidosis
Hx of possible underlying cause: tissue hypoperfusion, diabetes, medication (e.g., metformin, paraldehyde), genetic defects (e.g., MELAS syndrome: mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes).May have physical findings relating to underlying cause.
Wide anion-gap metabolic acidosis together with elevated serum lactate level confirms diagnosis.
Iron toxicity
Hx of anaemia may be present (exposure to iron tablets and/or repeated blood transfusions pose risk of toxicity).GI effects are common and include nausea, vomiting, diarrhoea, and abdominal pain.
Elevated serum iron level.

Salmonellosis

Shigellosis
Diarrhoea, often bloody.Usually due to faecal-oral contact or ingestion of contaminated food or water.Most commonly seen in children <5 years of age.
Identification of Shigella species in the stool.
Campylobacter species infection
Acute diarrhoea.Usually due to ingestion of infected food, most commonly undercooked poultry.
Identification of Campylobacter species in the stool.
Yersiniosis
Diarrhoeal illness that is usually due to ingestion of undercooked meat, especially pork.Most commonly causes an enterocolitis in young children, who often have bloody stools. Older children may also get terminal ileitis and mesenteric adenitis that cause appendicitis-type symptoms. Adults with yersiniosis get a gastroenteritis with diarrhea and abdominal pain.
Identification of Yersinia species in the stool.
Escherichia coli infection
Diarrhoea, often bloody.Most commonly a foodborne illness.
Identification of E. coli in the stool.
Vibrio species infection
Diarrhoea, often profuse and watery.Skin infection may be present.Associated with the consumption or handling of raw or undercooked shelfish or traumatic exposure to salt water.
Identification of Vibrio species in the stool.
Listeriosis
Diarrhoeal illness usually associated with poor hand hygiene and ingestion or handling of infected food.Typically affects neonates, pregnant women, older adults and immuncompromised people.
Identification of Listeria monocytogenes in the stool.
Gastroenteritis caused by viruses such as norovirus, rotavirus, astrovirus, or adenovirus
Viral gastroenteritis often has predominantly upper GI symptoms such as nausea and vomiting, but may also manifest as diarrhoea.
Differentiation is made by obtaining stool studies and identifying the causative organism.
Gastroenteritis caused by parasitic agents such as Cryptosporidium or Cyclospora
Parasitic conditions typically have a longer duration of illness.Epidemiological clues to a parasitic cause may include travel and exposure histories, but Salmonella also may be acquired both locally and in tropical locations.
Differentiation is made by obtaining stool studies and identifying the causative organism.
Gastroenteritis by preformed toxins (staphylococcal) or food poisoning
Presents with mostly upper GI symptoms and has a short incubation period of usually 2 to 4 hours.
Differentiation is made by obtaining stool studies and identifying the causative organism.

Sarcoidosis

Tuberculosis
History of exposure or high-risk patients.Differential diagnosis is especially challenging when patients present with upper lobe infiltrates, fever, and weight loss.
Positive PPD.Smear or culture positive for TB.Caseating granulomas on lung biopsy.
Histoplasmosis
History of living in an endemic area (e.g., the Mississippi River valley).
Fungus isolation on silver stain from lung biopsy.Positive urinary Histoplasma antigen.The most common finding on CXR is pulmonary nodules, can also present as infiltrates, lymphadenopathy, fibrosis, and thickened pleura. [19]
Non-small cell lung cancer
More likely to have a history of smoking.More pronounced haemoptysis and weight loss.
Lung mass on CXR.Malignant cells on lung biopsy.
Lymphoma (Hodgkin's and non-Hodgkin's)
Extrathoracic involvement is more common (cervical and supraclavicular lymphadenopathy).
Biopsy of mediastinal lymph nodes shows features of lymphoma.
Berylliosis
History of occupational exposure to beryllium in nuclear and aerospace industries.
Non-caseating granuloma on lung biopsy that is difficult to distinguish from sarcoidosis.Abnormal beryllium lymphocyte proliferation assay on serum or bronchoalveolar lavage fluid has a high positive predictive value in diagnosing chronic berylliosis. [20]
Hypersensitivity pneumonitis (chronic)
History of exposure to one of a multitude of agents (e.g., birds' feathers and droppings, compost, peat moss, metalworking fluids).Best described in farmers exposed to mouldy hay.
Positive precipitins to known antigens.CT chest shows poorly defined nodules in the acute phase and fibrosis with bronchiectasis in the chronic form.Poorly formed granulomas and intra-alveolar foci of organising pneumonia on lung biopsy.CD8 cell predominance on bronchoalveolar lavage. [21] [22]

SARS

Community-acquired pneumonia
Lack of recent travel history to an affected area or of recent close contact with a person confirmed with or suspected of having SARS.
Sputum and blood cultures: may be positive for Streptococcus pneumonia or other bacterial pathogens.FBC: leukocytosis and/or elevated neutrophil count. Clinical and radiological improvement with proper antibiotic therapy.
Viral respiratory infections
Lack of history of recent travel to an affected area or of recent close contact with a person confirmed with or suspected of having SARS.Unlikely to cause serious illness in young patients with no comorbidities. Upper respiratory symptoms are usually present.
Nasopharyngeal virus culture and direct fluorescent antibody/ELISA: may be positive for such pathogens as influenza viruses (A and B), respiratory syncytial virus, parainfluenza viruses, and adenovirus.Serology: useful for retrospective diagnosis.
Atypical pneumonia
Lack of history of recent travel to an affected area or of recent close contact with a person confirmed with or suspected of having SARS.Mild respiratory illness, often occurring in young people following exposure in close community settings.
Serology, PCR, or culture of nasopharyngeal swabs for Chlamydia and Mycoplasma pneumonia.Sputum culture or direct fluorescent antigen detection for Legionella pneumophila.Rapid urinary Legionella antigen detection.
Avian influenza infection
Difficult to distinguish from SARS based on symptomatology as both cause a febrile lower respiratory tract illness. Historical risk-factors may prove useful as avian influenza is more commonly associated with travel to a country affected with avian influenza A (H5N1) virus or direct contact with poultry or birds that may be carriers of H5N1.
Pharyngeal swab: positive reverse-transcription polymerase chain reaction (RT-PCR) for H5-specific RNA.Immunofluorescence antigen test: positive for antigen of H5N1 virus.Viral culture: growth of H5N1.Serological testing: positive for H5N1-specific antibody.

Scabies

Impetigo
Most frequently occurs in early childhood.Macules, which develop into vesicles and form golden-yellow crusts.Most often affects exposed areas on face, hands and extremities.
Biopsy: subcorneal pustules filled with neutrophils and occasional acantholytic cells. Sometimes Gram-positive cocci may be identified in the pustule or on the surface of the crusts. The dermal infiltrate usually contains perivascular lymphocytes and neutrophils. [18] [19]
Xerotic dermatitis
Symmetric areas of xerosis with diffuse scale.Worsens in severity distally (forearms > proximal arms).Linear burrows not seen.
No differentiating tests.
Folliculitis
Multiple follicular-based erythematous papules or pustules on chest and back.No burrows seen on physical examination.
Biopsy: intra- and perifollicular infiltrates rich in neutrophils. Follicular rupture with mixed infiltrates and granulation tissue is common. Bacterial and fungal micro-organisms may be seen. [18] [19]
Allergic contact dermatitis
May have a suspected exposure.Characteristic distribution depending on location of contact with allergen.Usually characterised by scaly patches without burrows.Pruritus tends not to be increased at night.
No differentiating tests.
Dermatitis herpetiformis
Chronic relapsing eruptions of grouped symmetrical, pruritic papulovesicles on scalp, neck, extensors and buttocks.May have gastrointestinal symptoms consistent with coeliac disease. [20]
Biopsy of dermatitis herpetiformis will show neutrophils in the dermal papillae on haematoxylin and eosin (H&E) stain sections and granular foci of IgA in the dermal papillary tips on direct immunofluorescence. [20]
Bullous pemphigoid
Tense bullae on torso and/or extremities.Scabies preparation, biopsy for H&E, and immunofluorescence are helpful in distinguishing these conditions.
Biopsy of bullous pemphigoid will show a sub-epidermal bulla with a predominantly eosinophilic infiltrate on H&E stain, and direct immunofluorescence of peri-lesional skin will show linear IgG and C3 at the dermal-epidermal junction. [21]
Pruritic urticarial papules and plaques of pregnancy
Urticarial and papular lesions seen in pregnant women in third trimester.Associated with greater than average weight gain and abdominal distention.Begins in abdominal striae and spares the umbilicus. [22]
No differentiating tests.

Schistosomiasis

Crohn's disease
Lack of exposure history to endemic areas for schistosomiasis.Crohn's disease (CD)-specific manifestations, including mouth ulcers and fistula formation, are not commonly found with schistosomiasis. Additionally, extra-intestinal manifestations such as arthritis, erythema nodosum, uveitis, and pyoderma gangrenosa are not found with chronic schistosomiasis.
Colonoscopy is the preferred test to differentiate schistosomiasis from CD. CD is defined by deep geographic and serpiginous ulcers. In contrast, chronic schistosomiasis colonoscopy may demonstrate normal-appearing colonic mucosa, necessitating tissue biopsy for diagnosis. On tissue biopsy, granulomas may be present with both diseases. However, in CD these granulomas do not contain any eggs. Typically the inflammation in CD is transmural, whereas that associated with schistosomiasis is localised around the egg-containing granulomas.Additionally, upper gastrointestinal series with small-bowel follow-through can be used to examine the small intestines for CD-related inflammation and narrowing of the lumen. A barium enema can be used to demonstrate ulcer depth and any fistulae. CT scan and MRI can also be used for examining the intestines, especially for CD complications such as abscesses, obstruction, or fistulae.
Ulcerative colitis
Lack of exposure history to endemic areas for schistosomiasis.Ulcerative colitis (UC) patients can exhibit extraintestinal manifestations such as aphthous ulcers, uveitis, arthritis, ankylosing spondylitis, erythema nodosum, or clubbing, which are not found with chronic schistosomiasis.
Colonoscopy is the preferred test to differentiate chronic schistosomiasis from UC. UC is defined by continuous shallow ulcers often with pseudopolyps limited to the colon and rectum. Biopsy demonstrates shallow mucosal ulcerations without eggs.
Colon cancer
Lack of exposure history to endemic areas for schistosomiasis.A family history of colon cancer, adenomatous polyposis, smoking, or long-standing ulcerative colitis or Crohn's disease increases the suspicion for colon cancer.
Colonoscopy is the preferred test to differentiate chronic schistosomiasis from colon cancer. On endoscopy of patients with colon cancer, colonic mucosa often contains polyps that on histological investigation demonstrate neoplastic cells and the absence of Schistosoma eggs.
Malaria
Travel to malaria endemic area.Malaria characteristically has a more abrupt onset of high fever of approximately 40\u02daC (104\u02daF) with profound malaise, headache, and fatigue.
Giemsa-stained thick and thin blood smears showing parasitised erythrocytes.Positive result for malaria antigen detection assay.
Salmonella infection
Salmonellosis can be confused with acute or chronic schistosomiasis. With Salmonella infection, 'rose spots' frequently occur 7 to 10 days into the febrile course of untreated S typhi infection, but are less common with enteric fever caused by other Salmonella species. A reactive arthritis can also develop that is not associated with acute or chronic schistosomiasis.Persistent or recurrent Salmonella bacteraemia has been associated with chronic schistosomiasis in endemic areas. [43]Concurrent salmonella and schistosomiasis infections may also occur in advanced HIV infections as an AIDS-defining illness. [43] [44] [50]
Positive blood cultures and serological testing for Salmonella.Salmonella may be cultured from stool.
Visceral larva migrans (toxocariasis)
Lack of exposure history to endemic areas for schistosomiasis. Toxocariasis occurs around the world and is typically a disease of children. Risk factors include exposure to contaminated soil, presence of unwormed puppies in the home, unhygienic conditions, and geophagia (pica) in children.Pruritus associated with toxocariasis is often more pronounced than that associated with acute schistosomiasis. Ocular larvae migrans can occur and affect visual acuity or cause unilateral blindness, which is rarely seen with schistosomiasis.
Positive serological test specific for anti-Toxocara species antibodies. [51]
Visceral leishmaniasis
Lack of exposure history to endemic areas for schistosomiasis; 90% of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil.History of chronic nodular or ulcerating skin lesions and isolated splenomegaly.
Splenic or bone marrow aspirates demonstrating amastigotes.Positive serological test specific for leishmaniasis.

Schizophrenia

Substance-induced psychotic disorder
Substance-related disorders are great imitators of psychopathology. Delusions are not as crystallised as in schizophrenia, but auditory hallucinations may still be present. A drug history should include evaluation of the duration, frequency, dosage, and time since last use. [62]The drugs most often associated with psychosis are heavy and persistent use of marijuana; stimulant drugs such as methamphetamine, cocaine, and amphetamines; psychotomimetics such as LSD and ketamine-like drugs; and inhalants such as toluene, gasoline, and various types of glues.Past history of extensive use may result in long-term persistent psychotic symptoms, years after the last exposure.
Urine drug screen identifies the causative drug.
Dementia with psychosis
Delusions may be similar, but are without a history of psychosis prior to dementia onset. An older age, family history of dementia and gradual cognitive decline suggests dementia.
CT or MRI of the head may reveal characteristic signs of the causative dementia.
Depression with psychosis
Depression typically occurs before psychotic symptoms appear. In schizophrenia, the psychotic symptoms occur first.
Clinical diagnosis
Bipolar disorder with psychosis
Typically, the mood disorder occurs before psychotic symptoms appear. In schizophrenia, the psychotic symptoms occur first.
Clinical diagnosis.
Malingering and factitious disorders
Patients may need constant reassurances due to consciously or unconsciously feigned physical symptoms.Particular attention should be given to any inconsistencies in history, atypical disease presentations, and evasiveness when asked about symptom details.Helpful to get collateral information from other carers or close contacts.Should be distinguished from somatisation; schizophrenics with true somatisation are not typically evasive or needy of reassurances.
Clinical diagnosis.
Delusional disorder
Patients suffer from a singular delusion but do not meet DSM IV-TR criteria for schizophrenia.
Clinical diagnosis.
Brief psychotic disorder
This disorder is differentiated by a short duration of psychosis (<1 month), unaccompanied by a functional deterioration.
Clinical diagnosis.
Pervasive developmental disorder (PDD)
A schizophrenia diagnosis is given in patients with PDD only if prominent delusions and hallucinations occur for at least 1 month (or less if treated successfully).Clinicians should gather a childhood history, looking for pervasive deficits.In PDD, the debut of deviant interpersonal interactions, delayed and aberrant communication skills, and limited repertoire of activities and interests occurs in the first years of life. Childhood schizophrenia (before age 5) is rare, even though patients with PDD may experience hallucinations at one time or another.
Clinical diagnosis.
Organic psychosis
Numerous medical conditions can cause psychiatric symptoms. Conditions affecting the brain can cause psychosis, such as epilepsy, tumours (not only brain tumours), traumatic brain injuries, HIV, neurosyphilis, pellagra, B12 deficiency, herpes encephalitis, and Wilson's disease, among others. History and physical examination help differentiate diagnoses.
Laboratory studies will help differentiation, such as RPR, HIV test, HSV-PCR in CSF fluid, copper urine level, ceruloplasmin in blood and vitamin B12 level.
Carbon monoxide poisoning
Psychosis due to carbon monoxide is without a long history of psychosis as in schizophrenia. A careful history should be taken, looking for possible toxic exposure.
Toxic screen for carboxyhaemoglobin may be performed in the emergency department.
Heavy metal poisoning
Psychosis due to heavy metals (e.g., bromide, mercury) is without a long history of psychosis as in schizophrenia.A careful history should be taken, looking for possible toxic exposure. Psychosis may present suddenly and, when exposure is treated, symptoms will remit.
Toxic screen for a bromide or mercury level may be performed in the emergency department. A serum bromide test will show results of >50 mg.
Medicine-induced psychosis
Some patients are more susceptible to psychosis and confusion with prescribed medicines.Steroids, anticholinergics, disulfiram, digitalis, and L-dopa medicines are the most common causes.A careful review of a patient's medicines, including OTC drugs, should be taken.
Symptoms resolve on withdrawal of the offending agent.A quantitative level of agents should be taken if available.
Liver diseases (e.g., hepatitis, cirrhosis)
Fatigue, anxiety, depression, and irritability are associated with physical signs of liver dysfunction.
Liver function tests exhibiting abnormal results.
Hyperthyroidism
Psychosis is accompanied by physical signs such as tachycardia, goitre, unexplained weight loss, palpitations, tremor, muscle weakness, or unexplained protrusion of the eyes (in Graves' disease).
Elevated serum T3 and T4 with a low TSH.
Hyperparathyroidism
May precipitate psychosis. [63] [64] [65]Anxiety and depression are commonly seen.Physical symptoms and signs may include bone pain, fractures (due to osteoporosis), poor sleep, fatigue, renal colic due to nephrolithiasis, myalgias, paraesthesias, and muscle cramps.Signs of the cause may be present, such as a hard and dense neck mass or a jaw mass, features of chronic renal failure, or features of a malabsorption syndrome.
Serum calcium is normal or elevated in primary hyperparathyroidism and decreased in secondary hyperparathyroidism.Serum PTH is elevated in primary and secondary hyperparathyroidism.

Scoliosis

Congenital scoliosis
Presents with a clinically evident spinal deformity at a much younger age. [2] [1]
PA and lateral x-rays: vertebral or rib abnormalities.
Neuromuscular scoliosis
Spinal deformity presenting in patient with an underlying neurological or muscular disorder that is usually evident by abnormal developmental history or examination findings.Neurological examination shows motor weakness, spasticity, or difficulties initiating or controlling motor activity, indicative of upper motor neuron lesions.Gait assessment reveals abnormalities related to muscle weakness or difficulty with initiation and control of motor activity.
EMG and nerve conduction testing: evidence of upper motor neuron lesions.MRI of brain: to evaluate the aetiology of the abnormalities found on physical examination.
Syringomyelia
May present in a very similar manner to adolescent idiopathic scoliosis (AIS).Earlier onset, with atypical curve patterns and significant curve magnitude at presentation. Subtle neurological abnormalities of asymmetric or hyperreflexive deep tendon reflexes, clonus, a positive Babinski, and abnormal or asymmetric abdominal reflexes.
MRI: in patients where there is concern, it is recommended to obtain an MRI of the entire spine to evaluate for an abnormality that may be causing the deformity.If the abnormality is large enough to be the cause of the patient's presentation/deformity, it should be identifiable on MRI.
Spina bifida
In cases where the condition is severe enough to cause spinal deformity, neurological abnormalities such as sensory and motor deficits corresponding to the level of the deformity usually co-exist.
Plain films and advanced imaging modalities (e.g., MRI): to reveal incomplete union of the posterior elements of vertebral levels demonstrating various degrees of failure of neural tube closure.
Arnold-Chiari malformation (tethered spinal cord)
Clinical features range from headaches to identifiable neurological abnormalities such as an abnormal gag reflex and sensory and motor deficits corresponding to the level of the abnormality.
MRI of the entire spine: to evaluate for an abnormality that may be causing the deformity, such as a tethered spinal cord or an abnormal position of the hindbrain in relation to the foramen magnum (tonsillar herniation).
Leg-length discrepancy
Results in the development of a compensatory spinal curvature to balance the trunk over the lower extremities.Examined in both standing and sitting positions. Assessment on sitting allows the pelvis and spine to balance without the influence of the leg-length discrepancy, thus correcting the observed spinal deformity. This would not occur in the presence of scoliosis.
Orthoroentgenogram: to quantify the degree of leg-length discrepancy.After determination of leg-length discrepancy, repeat standing x-rays with the patient standing on a block to account for the discrepancy demonstrates correction of the postural abnormality.

Seasonal affective disorder

Major depressive disorder, single and recurrent episodes
Meets DSM-IV-TR diagnostic criteria for recurrent major depressive episodes with a non-seasonal or predominantly non-seasonal pattern.Autumn- or winter-onset SAD may be characterised more by atypical depressive symptoms, with symptom remission during the spring or summer months.Major depressive episodes may be initiated by external stressors, whereas the SAD specifier is only temporally related.
Structured clinical interview.
Bipolar I and II disorders
Meets DSM-IV-TR diagnostic criteria for manic (bipolar I) or hypomanic (bipolar II) episodes with a non-seasonal or predominantly non-seasonal pattern.Spring- or summer-onset of manic or hypomanic symptoms tends to be uncommon.When this occurs in people with the SAD specifier, symptoms remit during the autumn or winter months.
Structured clinical interview.
Dysthymic disorder
At least a 2-year history of persistent, low-grade depressive symptoms.SAD shows a temporal pattern of onset and remission, whereas dysthymic disorder is chronic.
Structured clinical interview.
Cyclothymic disorder
At least a 2-year history of persistent, hypomanic symptoms and depressive symptoms that do not meet DSM-IV-TR criteria for a major depressive episode.SAD shows a temporal pattern of onset and remission, whereas cyclothymic disorder is chronic.
Structured clinical interview.
Premenstrual dysphoric disorder
Similarly to autumn- or winter-onset SAD, is characterised by atypical depressive symptoms. However, premenstrual dysphoric disorder may also be associated with bloating and breast tenderness with onset during the later part of the luteal phase of the menstrual cycle and remission of symptoms during the follicular phase.
Structured clinical interview.
Chronic fatigue syndrome
Characterised by persistent fatigue and other associated symptoms (e.g., musculoskeletal pain, sleep disruption, memory impairments, over-exertion) lasting at least 6 months.SAD shows a temporal pattern of onset and remission, whereas chronic fatigue syndrome tends to be chronic.
Structured clinical interview.
Hypothyroidism
Depressive symptoms may be similar to SAD, although atypical depressive symptoms are more common in SAD.Hypothyroidism has persistent symptoms and does not show a seasonal pattern.Hypothyroid depressive symptoms respond to TSH medicines.May show other features of hypothyroidism such as cold intolerance, constipation, dry skin/hair, goitre, or delayed return of deep tendon reflexes.
Serum TSH is high in primary hypothyroidism.
Substance abuse
Central nervous system depressants may produce depressive symptoms similar to SAD.Atypical depressive symptoms more common in SAD.Stimulants may produce manic or hypomanic symptoms similar to SAD.Substance-induced symptoms show onset with substance use and remit after the substances have been metabolised by the body.
Urine and blood testing for illicit substances.
Alcohol abuse
Alcohol use may produce depressive symptoms similar to SAD.Atypical depressive symptoms more common in SAD.Alcohol-induced symptoms show onset with alcohol use and remit after the substances have been metabolised by the body.
Urine and blood alcohol testing.Structured clinical interview.

Seborrhoeic dermatitis

Psoriasis
May mimic or be indistinguishable from scalp SD to the extent that the term 'sebopsoriasis' is employed.Nail pitting, intergluteal pinking (erythematous plaques of the intergluteal fold), arthralgia, and the extensor distribution of psoriatic plaques are characteristic features.
No established differentiating tests, but dermoscopy may be helpful. [8]
Actinic keratosis
May appear as an erythematous papule with scale more firmly adherent than that of SD.Palpated more easily than visualised and has a roughened quality on palpation.
Skin biopsy shows proliferating atypical squamous cells.
SLE
Sub-acute SLE may have similar clinical features.SLE plaques are less scaly, carmine-coloured, and have a more firmly adherent scale.
Skin biopsy shows perivascular cellular infiltrate. Direct and indirect immunofluorescence (IF) tests reveal immunoglobulin deposition.Serum ANA and anti-ENA may be positive.
Tinea capitis
Scalp scaling with or without hair loss.Common in pre-adolescent children, unlike SD.May not be inflammatory or erythematous.Pre-adolescent children with apparent SD should be suspected of having tinea capitis.
Potassium hydroxide preparation of scale for branching hyphae. Biopsy also shows hyphae. Culture is positive for Malassezia.
Histiocytosis X
SD-type scaling with fine erythematous papules.
Skin biopsy shows a dermis with S-100 positive histiocytes.
Acne rosacea
Central facial erythema with papules and pustules.
Skin biopsy does not show changes of SD.May show granulatomous changes.
Dermatitis, atopic
Erythema of face in infants, of antecubital fossae in older patients. History of atopy.
Skin biopsy does not show changes of SD.Has uniform epidermal spongiosis.
Leiner's disease
Familial pattern.Failure to thrive.Diarrhoea.Recurrent infection with gram-negative organisms.Erythroderma common.Has been attributed to an inherited dysfunction or deficiency of complement C5. [9]
The laboratory assay measures uptake of a particle that requires C5 for total opsonisation. [9] Phagocytic assays using such particles as erythrocytes, pneumococci, or latex particles are said to be inadequate screening procedures for C5 deficiency.
Impetigo
Characteristic golden crusts typically seen on face.May be secondary to other cutaneous disorders such as SD.
No differentiating tests.
Dermatitis, contact
Dermatitis at site of contact, often sharply demarcated.Allergen may be cryptic.
Patch testing may aid identification of the offending agent.
Acne vulgaris
Facial erythema with comedonal formation, papules, and pustules.
No differentiating tests.
Lichen planus
Violaceous polygonal papules associated with oral leukoplakia.
No differentiating tests.
Erythroderma
Red man syndrome may be due to a flare of SD but can also arise from pre-existing dermatoses, underlying lymphoma or other cancers, and drug eruptions, or it can be idiopathic.
No differentiating tests.

Seborrhoeic keratosis

Malignant melanoma
Malignant melanoma is the most important differential diagnosis of seborrhoeic keratosis. Sometimes differentiating between seborrhoeic keratosis and melanoma is a challenge. A key feature is that a melanoma tends to vary more in colour, such as brown, blue, black, grey, and red, whereas a seborrhoeic keratosis usually is limited to shades of brown and black.Melanoma usually has a smooth surface that can vary in height, while seborrhoeic keratosis usually looks the same across the whole surface. Melanoma does not generally have the warty, 'stuck-on' appearance of seborrhoeic keratosis. [1] [2] [3] [13]Melanoma is less uniform and less symmetrical in colour and shape than seborrhoeic keratosis.
Dermatoscopy: dark pigmentations forming an asymmetric ring around follicular openings, slate-grey dots and areas of irregular, broadened network. Also, biopsy and histopathological examination are used to differentiate.
Viral warts
More commonly located on hands and feet.
Dermatoscopy: warts appear to be embedded in the skin, rather than 'pasted on', and are grey-brown or flesh-coloured, while seborrhoeic keratosis can be tan, brown, or black.
Nevus
Most nevi develop during the first 20 years of life; seborrhoeic keratoses usually develop in people older than 30 years and become more common with advancing age.
Dermatoscopy shows a heterogenous globular pattern.
Pigmented basal cell carcinoma
Arise on sun-exposed areas of light-skinned individuals, most frequently on the head and neck. [2] [14] Lesions commonly occur in older adults (fourth decade and older). Clinical characteristics vary with the histopathological subtypes. The most common type of basal cell carcinoma is the nodular basal cell carcinoma. Characteristic symptoms of nodular basal cell carcinoma are bleeding and crusting.The second most frequent subtype of basal cell carcinoma is the superficial basal cell carcinoma. Morpheaform/infiltrative/sclerosing basal cell carcinomas are more infrequent than the other subtypes but more aggressive and locally destructive. They have a depressed, whitish scar-like appearance. [2] [14]
Dermatoscopy, biopsy. Nodular basal cell carcinoma appears as well-circumscribed pearly pink or translucent papule with varying degree of pigmentation. Often well-demarcated telangiectatic vessels are seen on the surface.Superficial basal cell carcinoma appears as an erythematous scaly plaque or patch, most commonly found on the torso.
Squamous cell carcinoma and Bowen's disease
Squamous cell carcinoma appears as hyperkeratotic, superficially erosive or ulcerated plaques or papules on severe sun-damaged skin.
Dermatoscopy: appears as hyperkeratotic, superficially erosive or ulcerated plaques or papules.
GI tract adenocarcinoma
The Leser-Trelat sign is the appearance of a high number of seborrhoeic keratoses over a short time interval, especially on the torso. [3] [5] [15] [16] It is a paraneoplastic syndrome mostly associated with a GI tract adenocarcinoma (45% of cases). It is often associated with metastatic spread of the primary tumour and with a poor prognostic outcome of the affected patients. Approximately 100 cases of Leser-Trelat have been reported in the literature. The seborrhoeic keratosis may precede, follow, or develop concurrently with the beginning of the symptoms of the cancer. Involution of the seborrhoeic keratoses after successful treatment of the cancer has been described.
Tumours visible with imaging; tests for tumour markers.
Lymphoproliferative disorders
Associated with the Leser-Trelat sign, where a high number of seborrhoeic keratosis lesions emerge over a short time interval, especially on the torso. [3] [5] [15] [16]
Tumours visible with imaging; tests for tumour markers.
Benign neoplasias
Associated with the Leser-Trelat sign, where a high number of seborrhoeic keratosis lesions emerge over a short time interval, especially on the torso. [3] [5] [15] [16]
Tumours visible with imaging; tests for tumour markers.
Pregnancy
Associated with the Leser-Trelat sign, where a high number of seborrhoeic keratosis lesions emerge over a short time interval, especially on the trunk. [3] [5] [15] [16]
Pregnancy test: positive for human beta chorionic gonadotrophin in urine and/or blood in fertile women.

Secondary hyperparathyroidism

Primary hyperparathyroidism
Difficult to distinguish clinically from secondary hyperparathyroidism. Both types have constitutional symptoms and skeletal complaints. Kidney stones are a hallmark of the classical primary form, but may be absent. Laboratory values are essential for differential.
Low serum calcium in the presence of elevated parathyroid hormone distinguishes secondary hyperparathyroidism from primary hyperparathyroidism (high calcium).

Sepsis

Non-infectious causes of systemic inflammatory response syndrome (SIRS)
SIRS can result as a non-specific finding from a host of other disease states, including postoperative recovery, trauma, burns, transplant rejection, hyperthyroidism, Addisonian crisis, blood product transfusion reactions, serum sickness, immunisations, and CNS infarction or haemorrhages.
Specific tests are directed by clinical suspicion of underlying cause.Associated medical interventions (e.g., catheterisation, surgical procedures, ventilation) can subsequently lead to superimposed infections to make sepsis a continual threat and possibility.
Myocardial infarction (MI)
Symptoms suggesting MI are central, squeezing chest pain radiating down the left arm or into the jaw. Pain may be felt in the epigastric region.Patients may present in cardiogenic shock.
Ischaemic changes on ECG.Elevated CK-MB and troponin.
Acute pancreatitis
May present with abdominal pain and hypovolaemia.There may be a history of gallstones, alcohol use, or viral infections (e.g., mumps).
Elevated serum amylase, lipase, glucose; low calcium.
Massive pulmonary embolism
Presents with acute dyspnoea, pleuritic chest pain, and hypotension.
CT pulmonary angiogram shows a filling defect in the pulmonary arteries.
Leukemia
May present with fever, leukocytosis, anaemia, tachycardia, multi-organ dysfunction, and dyspnoea and thus meet diagnostic criteria for (suspected) sepsis.The immunocompromise may additionally facilitate development of infections or the increased clinical suspicion of undiagnosed infection.
Biopsies of blood smear, bone marrow, tumour, or lymph nodes may identify neoplastic cells.Identification of a specific infectious agent is definitive in differentiating sepsis from SIRS.
Malignant hyperthermia
This is a rare condition characterised by severe hyperthermia (>41.1°C [106°F]) and muscle rigidity following administration of anaesthetic agents (e.g., succinylcholine for intubation). Lactic acidosis, hyperkalaemia, rhabdomyolysis, hypoxia, and arrhythmias may also occur. [66]Malignant hyperthermia is an inherited disorder (autosomal dominant) and a high index of suspicion is necessary if there is a positive family history. [66]
The caffeine-halothane contracture test (CHCT) is most commonly used to screen for susceptibility, as ryanodine receptor gene (RYR1) identification is gaining in clinical importance. [67]The CHCT requires muscle biopsy and testing in select regional laboratories after resolution of the episode.Neither test is clinically useful to direct therapy in the acute situation.
Drug-induced fever and coma
This includes neuroleptic malignant syndrome, serotonergic syndrome, delirium tremens, and metformin lactic acidosis.History of causative drug use.
Clinical diagnosis. Specific tests are not readily available.

Septic arthritis

Osteoarthritis
Known history of osteoarthritis.Many joints symptomatic to a similar degree.
Synovial fluid aspirate will not reveal micro-organisms.
Psoriatic arthritis
Known history of inflammatory arthritis and psoriasis or family history of psoriasis.Many joints symptomatic to a similar degree.
Synovial fluid aspirate will not reveal micro-organisms.
Rheumatoid arthritis
Known history of rheumatoid arthritis.Many joints symptomatic to a similar degree.
Synovial fluid aspirate will not reveal micro-organisms.
Gout
Known history.
Synovial fluid polarising microscopy will reveal urate crystals.
Pseudogout
Known history.
Synovial fluid polarising microscopy will reveal pyrophosphate crystals.
Haemarthrosis
Known history of a bleeding diathesis.
Joint aspiration will reveal blood.
Trauma
History of trauma to the affected joint.
Joint aspiration may reveal blood.
Bursitis
Examination will reveal that the swelling is external to the joint. The joint itself will move freely and painlessly.
If the joint is aspirated no fluid will be obtained.
Cellulitis
Examination will reveal erythematous skin overlying the joint. The joint itself will be unrestricted.
If the joint is aspirated no fluid will be obtained.
Tuberculosis, extrapulmonary
There may be a history of immunocompromise, origin from an endemic area, or insidious onset of symptoms.
Synovial biopsy may show positive mycobacterial smears or cultures.
Lyme disease
There may be a history of erythema migrans or tick bite.
Lyme titre may be positive.

Serotonin syndrome

Neuroleptic malignant syndrome (NMS)
History of exposure to antipsychotics, unless patient is on multiple drugs including serotonergic agents.Slow onset of symptoms, usually over days.Bradykinesia, extrapyramidal effects, lead-pipe rigidity, and autonomic lability differentiate. [2]Absence of neuromuscular excitation.
Diagnosis is clinical. There are no differentiating tests.
Sympathomimetic toxicity
History of exposure to sympathomimetics.Absence of neuromuscular excitation.
Diagnosis is clinical. There are no differentiating tests.
Anticholinergic delirium
History of exposure to anticholinergics.Bowel sounds absent.Dry skin.Absence of neuromuscular excitation.
Diagnosis is clinical. There are no differentiating tests.
Malignant hyperthermia
History of exposure to anaesthetics.Occurs perioperatively.Absence of neuromuscular excitation.
Diagnosis is clinical. There are no differentiating tests.
Meningitis
Non-specific symptoms including neck stiffness and nausea/vomiting, photophobia, and rash.Kernig's or Brudzinski's signs may be present.Absence of neuromuscular excitation.
Investigations include CT/MRI head; CSF microscopy, Gram stain, cultures, and protein/glucose; and blood cultures.
Encephalitis
Focal neurological deficit, rash, and altered mental state.Absence of neuromuscular excitation.
Investigations include CT/MRI brain, blood cultures, throat swab (for viruses), and CSF analysis.
Non-convulsive status epilepticus
Absence of neuromuscular excitation.
Response to benzodiazepine.An EEG should be done in consultation with a neurologist.
Baclofen withdrawal
History of exposure to intrathecal baclofen.
Positive response to reintroduction of baclofen.

Severe combined immunodeficiency

DiGeorge syndrome
Abnormal development of the 3rd and 4th pharyngeal pouch, which includes the thymus.Spectrum of immune dysregulation varies, although a severe form results in severe T-cell lymphopenia.Associated defects commonly include palatal abnormalities, distinct facies, hypothyroidism, hypoparathyroidism, and cardiac defects. [11]
Confirmation requires deletion of 22Q11.2 by fluorescence in situ hybridisation (FISH) or DNA microarray on genetic testing. [17]
Omenn's syndrome
Considered a form of SCID. [11]Symptoms include eosinophilia, rash, and enlarged spleen and lymph nodes.
Flow cytometry will usually demonstrate increased CD4+CD45RO+ T cells (memory T cells) and markedly decreased CD4+CD45RA+ T cells (naive T cells).Molecular diagnosis requires identifying mutations in genes associated with this disorder such as hypomorphic mutations in recombination activating genes (RAG1 and RAG2), Artemis, and other genes.
Bare lymphocyte syndrome (BLS)
Symptoms include sinopulmonary infections and granulomatous skin lesions.
Flow cytometry shows decreases in the number of CD4+ T cells, CD8 T cells, and a lack of major histocompatibility complex (MHC)-I or MHC-II expression. [11]
Zeta chain-associated protein (ZAP) 70 deficiency
Autosomal-recessive condition characterised by a lack of CD8+ T cells. Patients have normal numbers of CD4+ T cells, although they often have defects in function due to the role of ZAP 70 in TCR signalling. [11]Considered a subset of SCID.Some patients have been described with palpable lymphadenopathy and normal thymic shadow. [11]
Flow cytometry shows decreased CD8+ T cells with normal B cells and normal NK cells.Confirmation of this diagnosis requires DNA sequence analysis of ZAP 70 gene.
NF-kappa-B essential modulator (NEMO)
Also called hypohidrotic ectodermal dysplasia with immune deficiency.Characterised by deficiencies in T-cell proliferation and abnormalities in NK cell cytotoxicity. [18]Symptoms include abnormal development of hair, teeth, and sweat glands.Patients are susceptible to mycobacterial and streptococcal infections.
Diagnosis is confirmed by mutation analysis. The underlying genetic defect is in the NEMO (I-kappa kappa gamma), which is involved in the activation of NF-kappa B. [11]
Hyper IgM syndrome (HIGM syndrome)
Presents in an identical manner to SCID.
Flow cytometry may show normal T-cell numbers.Serum IgM may be normal or elevated with reductions in IgG and IgA.Diagnosis confirmed with genetic studies, which show mutation in either CD40 or CD40 ligand (CD40L).
HIV-1
Maternal history of HIV-1 infection.Presents in an identical manner to SCID.
HIV PCR confirms diagnosis.

Sexual abuse and assault

Lichen sclerosus
Hour-glass configuration; chronic condition; hypo-pigmentation. [39]
Clinical diagnosis by a specialistSymptoms are relieved with steroid treatment
Urethral prolapse
Doughnut-shaped urethral mass with haematuria. [40]
Clinical diagnosis
Nevus
Persistent finding of brown or black papule or macule on repeat examination.
Clinical diagnosis
Haemangioma
Persistent finding of red nodule on repeat examination.
Clinical diagnosis
Molluscum contagiosum
Smooth umbilicated lesions.
Clinical diagnosis
Non-specific vaginitis
History of use of potential irritants (e.g., bubble bath); poor hygiene. Vaginal irritation may lead to friability and bleeding.
Clinical diagnosis
Vaginal foreign body
May present with vaginal discharge, vaginitis, or vaginal bleeding in toddlers and elementary school-age children. Toilet paper is most common foreign body. [41]
Clinical diagnosis

Shaken baby syndrome

Accidental head trauma
History of trauma: more major trauma such as window falls and motor vehicle accidents will usually be witnessed and documented by police or paramedics.Physical examination will usually reveal bruising related to a fall, although in some cases scalp bruising may be deep and therefore not visible externally.Ophthalmological examination is usually completely negative, although in crush injuries or instances where the eye received a direct blow there may be a small number of retinal haemorrhages.
CT head: although skull fracture and subdural haemorrhage may be present, it is rare for accidental household falls to result in significant brain injury.
Birth trauma
The incidence of asymptomatic parturitional trauma appears to range from 10% to 26% of all newborns, with decreasing frequency after forceps, vaginal, and caesarean deliveries. Resolves by 4 to 6 weeks of age. [40] [41]If a birth-related haemorrhage is severe enough to cause symptoms, this will occur in the newborn period. The new onset of symptoms and signs of inflicted traumatic brain injury in a child who was asymptomatic at birth is not consistent with birth-related subdural haemorrhage.Retinal haemorrhages are seen in 30% to 50% of births, are generally few in number, and present in the intraretinal layer. They can be bilateral and widespread; most resolve within 1 or 2 weeks, and the remainder are gone in 6 to 8 weeks. [27] [42] [43] Widespread retinal haemorrhages after 6 to 8 weeks of age are of concern for abusive head trauma.
Distinguishing between inflicted injury and birth trauma is based on historical factors of the birth as well as the current presentation of injury.
CNS infection: meningitis and encephalitis
Fever and clinical signs of meningismus.Generally, parents give hx of progressively worsening illness.
LP and CSF analysis: increased number of WBCs, visualisation of bacteria on microscopy, low glucose, high protein, positive culture for organism, positive serology for viruses.
Subdural bleeding into benign enlargement of the subarachnoid space (BESS)
Pre-existing condition of BESS may predispose infants to the occurrence of subdural bleeding with minor trauma.Usually asymptomatic, absence of retinal haemorrhages; no other signs of abuse.
Cranial imaging: enlargement of subarachnoid space with subdural bleeding that is often unilateral, not space-occupying, or associated with signs of brain oedema or injury such as contusion, diffuse axonal injury, or tissue shearing.
Glutaric aciduria type I
Positive FHx (autosomal recessive), microcephaly, motor delay, and mental retardation. [34] Retinal haemorrhages may be present.A genetics/metabolism team should be consulted if there is any possibility of glutaric aciduria type I. [25]
CT head: frontotemporal brain atrophy, subdural fluid collections that sometimes contain blood.Urine screen: increased levels of glutaric, glutaconic, and 3-hydroxyglutaric acids.
Osteogenesis imperfecta
Positive FHx (autosomal dominant), hx of fractures after minor trauma, discoloration of the sclera to a blue-grey colour (types 1 and 3), poor muscle tone.
Skin biopsy and culture of fibroblasts should be performed, enabling a collagen synthesis assay that may show quantitative or qualitative differences in collagen in patients with osteogenesis imperfecta.Mutation analysis of COL1A1 and COL1A2 genes from fibroblast RNA may also be performed.
Rickets
Clues in presentation depend on type of rickets. Nutritional deficiency is common if children are breastfed without vitamin D supplementation.Bone deformities of the forearms and posterior bowing of the distal tibia can occur in infants.
Typically low calcium and vitamin D levels in hypocalcaemic rickets; however, biochemical profile does vary depending on type of rickets.
Vitamin K deficiency
Haemorrhagic disease of the newborn due to vitamin K deficiency can be clinically indistinguishable from shaken baby syndrome.History of lack of administration of vitamin K at birth; drugs taken by mother including warfarin and certain anticonvulsants or antibiotics; or the presence of other medical conditions (intractable diarrhoea, alpha-1 antitrypsin deficiency, hepatitis or biliary atresia, cystic fibrosis, or the use of antibiotics) that result in poor absorption of oral vitamin K may be present. [44]
Prolonged PTT and activated partial prothrombin time (aPPT).
SIDS
Clinical absence of retinal haemorrhage and skeletal injury.
Autopsy negative for other causes of death.

Shigella infection

Non-Shigella bacterial diarrhoea
It is often not easy to differentiate between pathogens that cause bloody diarrhoea.Bloody diarrhoea is suspicious for Shigella or enterohaemorrhagic Escherichia coli.Other bacterial infections such as Campylobacter jejuni, Vibrio cholerae, Yersinia enterocolitica, and Salmonella may also cause bloody diarrhoea. [2]Watery diarrhoea often occurs with V cholerae.Clostridium difficile may rarely cause bloody diarrhoea. If risk factors such as previous antibiotic therapy or exposure are present, C difficile should be considered.
Stool cultures are useful to differentiate bacterial causes of diarrhoea.
Viral gastroenteritis
Viral causes of diarrhoea (such as norovirus, adenovirus, and rotavirus) do not usually cause bloody diarrhoea. In addition, vomiting tends to be a significant feature of these infections. [2]
Negative stool microscopy and culture along with clinical suspicion.
Parasitic diarrhoea
In developing countries, Entamoeba histolytica, Giardia intestinalis, Cryptosporidium parvum, and Cyclospora cayetanensis commonly cause diarrhoeal disease. [2]Parasitic diarrhoea in the developed world is uncommon and may be related to exposure during travel.Except in E histolytica infection, diarrhoea is not usually bloody.
Stool microscopy is useful to detect parasites.
Idiopathic inflammatory bowel disease
The course of idiopathic inflammatory bowel disease (Crohn's disease, ulcerative colitis, microscopic colitis) is often more protracted than that of shigellosis. [4] There may be a hx or FHx of the disease. Extra-intestinal manifestations of idiopathic inflammatory bowel disease may be present (e.g., skin lesions or fistulae).
Negative stool cultures and positive sigmoidoscopy findings suggest inflammatory bowel disease.
Coeliac disease
Persistent (>14 days) diarrhoea may prompt consideration of celiac disease. However, the diarrhoea is not bloody.
Positive celiac serology is diagnostic. If there is clinical suspicion, duodenal biopsy may be indicated after a gluten challenge.
Malignancy
May present with change in bowel habits, usually with loose stools.There may be a history of anorexia or weight loss. Patients are usually >45 years old.
Abnormal colonoscopy and evidence of a tumor or metastatic disease on CT studies characterise malignancy.

Shock

Simple hypotension
Hypotension alone may be entirely asymptomatic, has continuing absence of signs of hypoperfusion, and the patient remains well. With no changes over several hours, this excludes even mild or early shock.
ECG and routine laboratory panel fail to yield significant pathology after observation for some hours.
Syncope or pre-syncope
Syncope or pre-syncope differ from shock by duration of hypoperfusion.Repeat BP after 5 to 10 minutes is back to normal levels.
ECG may be done, with no acute changes apparent.

Short gut syndrome

Active Crohn's disease
Can be distinguished from short gut syndrome (SGS) by the presence of signs such as rash or joint pains.The distinction is important as active Crohn's disease is treated very differently from SGS.
Endoscopy shows mucosal inflammation and ulceration, typical findings of active Crohn's disease.C-reactive protein and ESR may be elevated but are not specific.
Coeliac disease
Dermatitis herpetiformis is a characteristic rash that, when present, is almost always associated with coeliac disease.Symptoms of coeliac disease recede when patients are placed on a gluten-free diet.
Immunoglobulin A-tissue transglutaminase shows elevated titres in coeliac disease.Small bowel biopsy is diagnostic and shows characteristic intra-epithelial lymphocytes, villous atrophy and crypt hyperplasia.
Small bowel malignancy
No differentiating signs or symptoms. Patients with Crohn's disease are at risk for GI malignancy, which can present with similar symptoms of diarrhoea, weight loss, and fatigue.
CT enterography or endoscopy is likely to reveal a small bowel tumour.
Bacterial over-growth
No clear differentiating signs or symptoms. Patients with bacterial over-growth often have symptoms of diarrhoea, weight loss, and malabsorption similar to SGS. More common in patients without an ileocaecal valve. Bacterial over-growth in the context of SBS has been poorly studied.
An empiric trial of antibiotics as a diagnostic test is commonly performed. [18]A positive hydrogen breath test is indicative of bacterial over-growth. [18]
Anorexia nervosa
Weight loss and malnutrition can be a consequence of a lack of appropriate food intake. A careful dietary history is required to eliminate this possibility.Anorexia nervosa can be distinguished by a history of psychiatric illness, a predominance of nausea, loss of appetite, or night-time diarrhoea.
Stool laxative testing to identify laxative abuse.Direct observation of oral intake.

Sialadenitis

Mumps
Unilateral or bilateral self-limiting swelling of the parotid gland. Orchitis or oophoritis may develop.
Usually a clinical diagnosis.IgM is positive for up to 4 weeks after infection, but testing should not be done in the first 3 days. May be falsely negative if previously immunised.
Sarcoidosis
Usually bilateral (although unilateral parotid swelling has been reported), persistent, and only rarely mildly painful. Called Heerfordt's syndrome when accompanied by fever, uveitis, and facial palsy.
Biopsy will show presence of non-caseating granulomas.Serum calcium level and 24-hour urinary calcium levels are often elevated.CXR: bilateral hilar lymphadenopathy with or without pulmonary infiltrates.Serum ACE levels are often elevated.
Tuberculosis
May demonstrate chronic productive cough, fatigue, weight loss, and fever. Painless swelling of parotid glands is clinically indistinguishable in the absence of radiographic evidence of node calcification.
CXR: Infiltrates, cavities, or consolidation often in the upper lobes with lymphadenopathy.PPD is usually positive.PCR-based salivary assay to find evidence of mycobacterium tuberculosis has far better detection rate than culture.
Parotid and submandibular tumours
Asymptomatic or symptomatic swelling of a salivary gland. Rapid growth, pain, ulceration, and facial palsy are suggestive of the presence of a malignancy. An indolent asymptomatic and growing mass is suggestive of the presence of a benign neoplasm, although lymphomas may display indolent behaviour.
CT scan will show a solid mass clearly distinct from the surrounding tissues. Abscess formation is uniformly absent. In the absence of any evidence suggesting the presence of inflammation, FNA cytology is warranted. The presence of sialolithiasis argues against a tumour diagnosis.MRI offers excellent resolution of soft tissue structures including tumour and its relationship to surrounding structures.
Dental abscess
Hx of toothache or recent dental surgery, bleeding gums, poor dental hygiene, and pain elicited when affected tooth is pressed into the gum.
Usually a clinical diagnosis.Dental x-rays may demonstrate presence of abscess.
Ludwig's angina
Hx of recent dental infection or impacted lower third molar (wisdom tooth).Presents as a rapidly progressive cellulitis of the soft tissues of the neck and floor of the mouth. May be accompanied by fever and significant stridor.
Usually a clinical diagnosis.Dental x-rays may demonstrate presence of abscess or impacted third molar.
Angio-oedema
Rapid onset of facial swelling may be accompanied by respiratory impairment with stridor or abdominal pain. May occur in a hereditary form or as a response to allergy.
Decreased levels of C2 and C4 serum complement levels.

Sickle cell anaemia

Gout
Presents with severe pain, swelling, and redness of the affected joint, which is often the metatarsophalangeal joint of the big toe.Gout can be seen in patients with sickle cell disease who have associated renal disease.
Joint aspiration shows negatively birefringent monosodium urate crystals.
Septic arthritis
Typically presents with fever and swelling of the affected joint.Suspect in sudden onset of monoarthritis.Patients at risk include those exposed to recent bacteraemia from pneumonia or UTI, or with history of IV drug use, rheumatoid arthritis, prosthetic joint, or immunocompromise.
Joint aspiration will show a purulent effusion, high WBC count, positive Gram stain, and positive culture.
Connective tissue diseases
May present with butterfly rash; photosensitivity; swollen, painful, and stiff metacarpophalangeal joints; anaemia; and vasculitis.
Serological work-up may show ANA and/or RF positivity.
Avascular necrosis
Presents with pain typically in the hip or shoulder and can be differentiated from a vaso-occlusive crisis by its chronicity.
MRI of the affected joint would show no difference between avascular necrosis caused by sickle cell disease and necrosis caused by other aetiologies (e.g., injury or joint dislocation).
Perthes' disease
Condition of childhood characterised by necrosis of femoral epiphysis. Usually seen in children 4 to 10 years of age.May be associated with thrombophilia. [17]
X-ray is diagnostic. Maybe difficult to distinguish from sickle cell osteonecrosis.
Acute abdomen
Vaso-occlusive crises owing to small infarct of the abdominal viscera must be differentiated from other acute abdominal disorders. For example, acute cholecystitis presents with RUQ pain (worse after eating fatty foods), nausea and vomiting, and a positive Murphy's sign. Meanwhile, acute pancreatitis typically presents with abdominal/epigastric pain that radiates to the back.
Amylase and lipase are elevated in pancreatitis. Abdominal ultrasound in pancreatitis may show ascites, gallstones, dilated common bile duct, and an enlarged pancreas. In cholecystitis, ultrasound may show gallstones or a thickened gallbladder wall.
Osteomyelitis
Painful bone episodes in sickle cell anaemia are clinically indistinguishable from those experienced in osteomyelitis.
MRI bone scans do not confidently differentiate the two conditions.Persistent pain localised to one area, especially in a febrile patient, suggests the possibility of osteomyelitis.Blood cultures positive for Salmonella species, Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenzae type b, or Escherichia coli favour diagnosis of osteomyelitis.
Trauma
Pain and signs of injury related to the site of trauma.
If trauma is suspected in a child who cannot communicate, imaging of the affected area is helpful, along with close observation.

Sjogren's syndrome

SLE
Photosensitivity more frequent in SLE. [19] Malar rash, non-specific fever, prominent arthralgia and myalgia out of proportion to joint findings. Weight loss may be seen when disease is active.
Positive anti-dsDNA antibodies.Homogeneous ANA more likely in SLE than Sjogren's syndrome, which more typically has a speckled ANA pattern.Anti-La much less likely in SLE.
Rheumatoid arthritis
Joint pains and morning stiffness, especially of hands and feet. Joint destruction and deformities possible.
RF and anti-CCP both positive.RF alone positive in about 50% of Sjogren's syndrome. [19]
Hepatitis C
May have none, may have history of exposure risk to contaminated blood. Chronic liver disease examination findings possible but not always present (enlarged or scarred liver, ascites, anasarca, jaundice, bleeding disorder, encephalopathy).
Hepatitis C serology positive.May also have abnormal liver function testing.
Systemic sclerosis (scleroderma)
Symmetric thickening and tightening of skin of fingers, possibly extending to entire upper extremity, and including face, neck, and trunk.
Positive for Scl-70 antibodies.Nucleolar pattern of ANA associated with scleroderma; however, homogeneous or speckled patterns also seen.
Hypothyroidism
May include weight gain despite decreased appetite, change in hair or skin texture.
Elevated serum TSH, decreased serum T4.
Fibromyalgia
Non-specific.
None.
Depression
May include mood changes, change in appetite, loss of interest in usual activities.
None.
HIV
History may include exposure risk factors such as unprotected sexual activity, intravenous drug use.
HIV testing positive.
Sarcoidosis
May include pulmonary symptoms such as cough, shortness of breath, bilateral hilar lymphadenopathy on chest imaging. Skin lesions may include nodules, erythema nodosum. Uveitis possible.
Biopsy of lesion positive for sarcoid.
Drug-induced sicca
History of oral contraceptive, antihistamine, beta-blocker, phenothiazine or atropine use.
None.
Idiopathic or age-related sicca
None.
Atrophic glands and extensive fibrosis on salivary gland biopsy.

Skull fractures

Intracranial haemorrhage
Typically presents with loss of consciousness or period of decreased alertness, potential seizure activity (or loss of bowel and bladder continence), headache, weakness or sensory changes, or changes in cognition, speech, or vision.
CT will show subdural/epidural fluid collection.In subdural haematomas, fluid is usually crescentic in shape and can cross suture lines; a midline shift may be noted.In epidural haematomas, fluid collection shows lenticular shape that does not cross suture lines.Cerebral swelling may be manifested as the loss of grey-white matter distinction. Subdural haematomas that have a hypodense 'swirl' inside them signify potential hyperacute haematoma with active bleeding. Diffusely hypodense and isodense subdural haematomas indicate chronicity.
Suture lines in children
No clinical evidence of injury, no hx of head trauma.
CT scan allows differentiation between fractures and sutures based on location and anatomy.
Cephalhaematoma
Hx of birth trauma.
CT scan should show soft-tissue haematomas in the absence of skull fracture in the vast majority of cases. [2] [26] [27] [30] [31]
Child abuse
Hx of previous hospital attendance for non-accidental injury.Signs and symptoms inconsistent with hx; unexplained bruising; faltering growth for age.Unexplained dental injury and/or the presence of torn lingual or labial frenae.
Ophthalmoscopy may show retinal haemorrhage.Skeletal survey may identify occult fractures.
Osteogenesis imperfecta (OI) and other bone fragility disorders
Positive FHx (autosomal dominant), hx of fractures after minor trauma or deafness, discoloration of the sclera to a blue-grey colour (osteogenesis imperfecta [OI] types 1 and 3), dental discoloration, poor muscle tone.
X-ray reveals wormian bones, reduced bone density, and evidence of multiple fractures.Mutation analysis of COL1A1 and COL1A2 genes from fibroblast RNA may also be performed. Genetic testing is possible in a few centres, but is expensive. Genetic testing is only recommended in OI types 2 and 4; other types are diagnosed clinically and radiologically.Skin biopsy and culture of fibroblasts may be performed, enabling a collagen synthesis assay that may show quantitative or qualitative differences in collagen in patients with OI.

Slipped capital femoral epiphysis

Hip fractures
History of significant trauma.
X-ray shows increased soft tissue shadow and displacement of the epiphysis in any direction.
Avascular necrosis
Age of onset typically seen at 30 to 50 years.Features of underlying disorder may be present (e.g., SLE, Cushing's disease).Can result from slipped capital femoral epiphysis in its own right.
In initial stages, MRI may show decreased intensity for both T1- and T2-weighted images.
Legg-Calve-Perthes' disease
Clinical features often similar to slipped capital femoral epiphysis (e.g., onset of pain, limp, restricted range of motion).
Plain x-rays may show sclerosis, cysts, or collapse of the femoral head.MRI shows high signal intensity on T2-weighted images and low signal intensity on T1-weighted images in the subchondral region.
Hip dysplasia
Caused by intra-uterine loss of contact between the fetal femoral head and acetabulum.May range from mild, asymptomatic cases to severe dysplasia with congenital hip dislocation.Moderate-to-severe dysplasia may predispose to early osteoarthritis, labral tear, or impingement, and present with findings secondary to one or more of these conditions.Patients with congenital dislocation have shortening of the involved leg and decreased hip range of motion.
Shallow, more vertically oriented acetabulum seen on plain films.
Osteomyelitis
Typically chronic or acute-on-chronic presentation with vague pain complaints.May have at-rest or night pain.Constitutional symptoms (fevers, chills, malaise) often present.Unremarkable hip examination possible if infectious process involves pelvis.
Elevated WBC, CRP, and ESR.Blood cultures may be positive for infective organism.Plain film x-rays may show changes consistent with chronic osteomyelitis in some cases.MRI associated with higher sensitivity and specificity in select patients.MRI shows increased signal intensity on T2-weighted images and intra-osseous/sub-periosteal abscess.
Septic arthritis
Severe pain with weight-bearing activities.May be accompanied by fevers, chills, and malaise.Resting position of hip flexion, abduction, and external rotation to relieve pain.Pain with passive range of motion on examination.
Plain x-rays may show increased joint space.Joint effusion seen on ultrasound.Joint aspiration for synovial fluid analysis and culture may yield positive culture.
Groin pain/pull
Pain on adduction, direct tenderness in groin.
Tenderness directly over the groin and adductor tendons; no external rotation deformity.
Ankylosing spondylitis
Spondyloarthropathy typically seen in young-to-middle-aged men.Hip joint involvement is common, often bilateral.Symptoms (stiffness, pain) are worse in the morning and improve during the course of the day.Low back and sacroiliac joints are also frequently affected.
Plain film x-rays of the hip and pelvis may demonstrate irregularities of the sacroiliac joints with erosive/sclerotic changes.Classic bamboo-spine appearance seen on spinal x-ray.
Stress fractures
History may indicate overuse injury (e.g., endurance athlete or military recruit).
X-rays show oedema or stress reaction in the region of the femoral neck.

Small bowel obstruction

Ileus
Less crampy abdominal pain; in association with other cause (e.g., postoperative, systemic infection, medications).
CT scan shows passage of contrast throughout the small bowel and into the rectum.
Infectious gastroenteritis
Vomiting, typically nonbilious.
X-ray shows gas throughout abdomen; stool cultures may be positive for viruses or bacteria.
Large bowel obstruction
Very distended abdomen; constipation progressing to obstipation.
X-ray shows a very dilated colon.
Intestinal pseudo-obstruction
Chronic condition; constipation; often associated with administration of neurologic medications.
X-ray and CT show gas throughout abdomen; massively dilated intestine.
Appendicitis
Pain in right lower quadrant with nausea; vomiting (nonbilious).
Ultrasound and CT may confirm diagnosis in most cases.
Pancreatitis
Steady pain in the upper abdomen; nonbilious vomiting; back pain.
Increased amylase; CT scan shows inflamed pancreas.

Small cell lung cancer

Non-small cell lung cancer
Most signs and symptoms are similar to SCLC. Typical features include cough, haemoptysis, chest pain, dyspnoea, and hoarseness (if recurrent laryngeal nerve paralysis). Frequently unwell-looking, short of breath, with signs of recent weight loss.Finger clubbing and hypertrophic osteoarthropathy may be present and are more common in non-small cell lung cancer compared with SCLC.
CT chest shows size, location, and extent of primary tumour; evaluates for hilar and/or mediastinal lymphadenopathy and distant metastases.Sputum cytology shows characteristic malignant cells. Specificity greater than 95%, sensitivity variable between 20% to 70%. More likely to be positive with central lesions compared with peripheral lesions.Flexible bronchoscopy plus biopsy provides pathological confirmation of diagnosis. Endobronchial masses can be biopsied with forceps. Endobronchial brushings, washings, and alveolar lavage increase the diagnostic yield. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes is now possible. Detection of small peripheral lesions (<2 cm) is improved by use of endobronchial ultrasound.
Carcinoid tumour
Often asymptomatic with normal physical examination. May cause cough, dyspnoea, haemoptysis, unilateral wheezing or post-obstructive pneumonia if tumour is endobronchial.
CT chest: 80% of carcinoid tumours appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and highly vascularised.Flexible bronchoscopy shows raised, pink, vascular, lobulated lesions. Endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis.
Metastatic cancer
Signs and symptoms depend on the location of the primary tumour and distant disease and may include pain, weight loss, malaise, cough, dyspnoea, clubbing, or focal wheezing. Physical findings may be present depending on the location and extent of the disease.
CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses. Lesions are often irregular and in the periphery of the lower lung zones.Sputum cytology may reveal characteristic malignant cells. Yield is higher with large endobronchial lesions or large masses.CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasise to the lung include melanoma; thyroid carcinoma; oesophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis.PET-FDG scan shows increased uptake in both primary and distant sites. Certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-fluorodeoxyglucose (FDG) uptake.Biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells. Bronchoscopy has a 100% yield for endobronchial lesions.CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells in some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of TTNA procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
Infectious granuloma
History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving).May feature cough, dyspnoea, haemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats. Many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium species, zygomycetes, and others.Non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis. Lymphadenopathy may be present with active disease.
CT chest typically shows lesions <2 cm diameter and round with smooth borders. Old granulomatous disease may feature central, laminated, or diffuse calcification patterns. Mediastinal lymphadenopathy without calcifications is sometimes present. Nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the 'halo sign' (ground-glass opacity surrounding the nodule). Occasionally, calcifications can be seen in the spleen or liver.Fungal serologies: positive during active infection. The exact role of fungal serologies in assessing lung nodules is unclear. However, they provide valuable evidence of exposure to histoplasmosis, cryptococcosis, aspergillosis, coccidioidomycosis, and mucormycosis.Flexible bronchoscopy and biopsy can provide sample for identification and culture and sensitivity of organism.CT-guided TTNA can allow biopsy of some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of TTNA procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.PET: usually negative (<2.5 standardised uptake values). May be falsely positive in active infectious processes.
Sarcoidosis
Cough, dyspnoea, fatigue, weight loss, fever, night sweats, rash, eye pain, photophobia, blurred vision, and red eye. Pulmonary examination is usually unrevealing. Can affect any organ, so physical findings depend on specific organs affected. Skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions.
CT chest: adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, although can be located throughout the lung.Flexible bronchoscopy and biopsy reveals presence of non-caseating granulomas. The identification of granulomas on tissue obtained by bronchoscopy should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy. The identification of granulomas on tissue obtained by TTNA should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.Laboratory markers: angiotensin-converting enzyme (ACE) elevation may be seen in sarcoidosis, but is non-specific and adds very little information.
Rheumatoid arthritis
Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity.
CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones. May show cavitation.Flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule. The identification of granulomas on tissue obtained should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause. Necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centred on necrotic inflamed blood vessels.Laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported.
Wegener's granulomatosis
Cough, chest pain, dyspnoea, haemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain.
CT chest shows solitary or multiple lung nodules. Airways are frequently affected.Flexible bronchoscopy shows necrotising granulomatous inflammation. The identification of granulomas on tissue obtained by bronchoscopy or TTNA should be performed by a pathologist and stained for infectious agents before assuming a non-infectious cause.CT-guided TTNA can provide access to some lesions inaccessible to flexible bronchoscopyLaboratory markers: anti-neutrophil cytoplasmic antibody (ANCA). ANCA testing results depend on the extent and severity of the disease. Generalised Wegener's granulomatosis demonstrates >90% C-ANCA or PR-3 positivity. Limited Wegener's granulomatosis demonstrates 60% ANCA positivity.
Hamartoma
Usually asymptomatic with no physical findings. One percent to 20% of lesions are endobronchial and can cause dyspnoea, wheezing, or recurrent infections, secondary to airway obstruction.
CT chest shows well-demarcated peripheral nodule, with an average diameter of 1.5 cm and a heterogeneous appearance due to its content of mesenchymal tissue content. Fat attenuation is common, with or without calcification. 'Popcorn' calcifications can occur in 20% of cases. Imaging findings classic enough to be considered diagnostic.
Arteriovenous malformation
Dyspnoea is uncommon. May cause haemoptysis, pulmonary bruit, arteriovenous communications, or haemorrhagic telangiectasia in the skin, mucous membranes, and other organs. Cyanosis and finger clubbing may be present. Neurological symptoms from cerebral aneurysms, cerebral emboli.
CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified. Most common in lower lobes. Multiple lesions in 30% of cases. Usually round or oval, ranging from 1 cm to several cm in diameter.Pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures. In cases of significant haemoptysis, pulmonary angiogram is combined with bronchial artery embolisation.Arterial blood gas analysis may show decreased pO2 and decreased oxygen saturation when AV flow is severe. In cases of severe systemic AVMs, chronic hypoxaemia may cause polycythemia.
Amyloidosis
Weight loss, paraesthesias, dyspnoea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms.Weight loss of >9 kg is common. Small vessel involvement can cause jaw or limb claudication, and rarely angina. Amyloid purpura is present in about 1 in 6 patients, typically peri-orbital. Eyelid petechiae are common. Hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree.
CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits.Serum immunofixation shows presence of monoclonal protein; seen in 60% of patients with immunoglobulin light chain amyloidosis (AL).Urine immunofixation shows presence of monoclonal protein; seen in 80% of patients with amyloidosis.Immunoglobulin free light chain assay shows abnormal kappa to lambda ratio. This relatively new test has extremely high sensitivity, over 90%, for diagnosing amyloidosis
Bronchiolitis obliterans organising pneumonia (BOOP)
Normally presents as a flu-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, non-productive cough, malaise, dyspnoea, and weight loss. Sometimes features pleuritic chest pain and haemoptysis.In most patients, auscultation reveals fine, dry lung crepitations. Finger clubbing is unusual.
CT chest is preferable to plain chest x-ray as it gives a better assessment of the disease pattern and distribution, and potential sites for biopsy. Typical features include: patchy 'ground-glass' opacities in a sub-pleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilatation; 3 to 5 mm diameter centrilobular nodules or other ill-defined nodules; mediastinal lymphadenopathy, pleural effusions.Pulmonary function tests typically show a restrictive pattern.Bronchoalveolar lavage (BAL) shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages, and occasional plasma cells. CD4+/CD8+ cell ratio is decreased. Also, the ratio of lymphocytes to CD8+ cells is significantly increased.Transbronchial lung biopsy, in combination with BAL, can be a useful approach, prior to possible open biopsy.Open lung biopsy is often required for definitive diagnosis.
Pulmonary tuberculosis
Cough longer than 2 to 3 weeks, discoloured or bloody sputum, night sweats, weight loss, loss of appetite, pleuritic chest pain.
Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates. Ipsilateral adenopathy, atelectasis from airway compression and pleural effusion can be seen. Reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe or superior segment of either lower lobe, with or without cavitation. As disease progresses it spreads to other segments/lobes.Sputum smear: positive for acid-fast bacilli (AFB). Sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis). Organisms other than M tuberculosis), especially non-tuberculous mycobacteria (e.g., M kansasii and M avium), may be positive for AFB stain.Nucleic acid amplification tests (NAAT) positive for M tuberculosis. DNA or RNA amplification tests for rapid diagnosis. May be used on sputum or any sterile body fluid. Several commercial tests are available. Results available in less than 8 hours in the laboratory. Useful in smear-positive disease to confirm that observed mycobacterium are M tuberculosis (95% sensitivity, 99% specificity) and in smear-negative disease for rapid diagnosis (50% sensitivity, 95% specificity). In suspected smear-negative cases, a moderate to high pretest probability should guide the decision to use NAAT.
Germ cell tumour
Occur mostly in men aged 20 to 40 years. About one third of patients are asymptomatic. Symptoms are related to the size of the lesion. May cause chest pain, breathing problems, cough, fever, headache, and fatigue.
CT chest: germ cell tumours account for about 10% to 15% of mediastinal tumours in adults and 25% of such tumours in children. Frequently located in anterior mediastinum. CT can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures. Seminomas appear as large, well-marginated, homogeneous, anterior mediastinal mass with soft-tissue opacity or attenuation that shows minimal contrast enhancementSerum tumour marker tests: alpha-fetoprotein (AFP), beta-human chorionic gonadotrophin (beta-hCG), lactate dehydrogenase (LDH). beta-hCG are elevated in 7% to 18% of patients. AFP levels are usually normal.
Non-Hodgkin lymphoma
Aggressive NHL lymphoma may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological examination. Low-grade NHL patients often minimally symptomatic or asymptomatic.
CT chest: frequently anterior mediastinum. Can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures.FBC with differential shows thrombocytopenia, pancytopenia.Blood smear shows nucleated red blood cells, giant platelets.Lymph node biopsy with immunohistochemistry shows characteristic cells. Preferably obtain excisional or core biopsy to provide information on lymph node architecture.
Hodgkin's lymphoma
Predominantly a disease of young adults. Most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain.
Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathyPET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging. Sensitivity reported to be 93% and specificity 87%.Lymph node biopsy with immunohistochemistry: the Hodgkin cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell.
Thymoma/thymic carcinoma
Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis. May also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness. May have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren's syndrome. About 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision)
Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography.CT chest: 90% occur in anterior mediastinum. CT is usually accurate in predicting tumour size; location; and invasion into vessels, the pericardium, and the lung. However, it cannot accurately predict invasion or resectability.Positron emission tomography (PET) may be of value in determining malignancy and extramediastinal involvement.Pre-operative biopsy is indicated if there are atypical features or if imaging suggests invasive tumour and patient is under consideration for induction therapy.
Bronchogenic cyst
Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age. Approximately 50% of patients are asymptomatic. In adults, chest pain (often pleuritic) and dysphagia (due to oesophageal compression) are the most common symptoms. May also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax.
Two-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina. Can appear as a solid tumour or show air-fluid level if cyst is infected or contains secretions.CT chest: frequently middle mediastinum, typically at level of the mediastinum. Cysts are thin-walled with smooth borders and may contain secretions, blood, or pus. Calcifications may also be seen.MRI: frequently middle mediastinum, typically at level of the mediastinum. T2-weighted images, shows a homogeneous mass of moderate-to-bright intensity. On T1-weighted images, lesions may vary in intensity depending on protein content of the cyst.
Tracheal tumours
Common symptoms include dyspnoea, cough, haemoptysis, wheeze, and stridor. Less commonly, hoarseness and dysphagia may be present.
Plain chest radiographs are generally insensitive for detection of tracheal tumours. Clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing, and post-obstructive pneumonia or atelectasis.Helical CT enables accurate calculation of tumour volumes and can help differentiate mucosal lesions from submucosal lesions.MRI can be useful in assessing extension into surrounding tissue and vascular anatomy.Bronchoscopy allows direct visualisation, opportunity for biopsy, and potential for laser treatment.
Thyroid mass
Symptoms and signs depend on size of mass. May be visible/palpable as lump on anterior aspect of neck. May present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat. May also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass.
Laboratory testing should include thyroid function panel, with TSH, free T4, free T3.I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism. A hyperfunctioning (hot) nodule is almost always benign. Most nodules are hypofunctioning (cold). Most of these are benign, but malignant nodules are also cold.Ultrasound and Doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s). Features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins. It can also guide fine-needle aspiration, which can reveal malignant cells or cyst fluid.CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer and extension of the scan into the chest can help evaluate a retrosternal thyroid mass.
Pneumonia/bronchitis
Clinical and radiological features of bronchitis or pneumonia should improve with appropriate treatment.Recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer.
CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray.Bronchoscopy can also be used to assess for endobronchial lesions or biopsy suspicious pulmonary masses.

Smoking cessation

Polysubstance abuse
Concomitant dependence on other addictive substances.
None.

Snoring

Upper airway resistance syndrome (UARS)
Fragmented sleep results in increased subjective and objective daytime sleepiness. Few clinical centres measure respiratory effort using oesophageal probes and therefore UARS is probably an under-diagnosed condition. [1]
UARS applies to individuals with increased inspiratory efforts (as identified by oesophageal pressure measurements) with frequent arousals, as measured from EEG during diagnostic overnight polysomnography (PSG), but without overt apnoeas and hypopnoeas.
Obstructive sleep apnoea (OSA)
Patients and partners often give a history of cessation of breathing for 10 seconds or more, as well as choking and gasping episodes. They are often obese and have excessive daytime somnolence.
A sleep study will diagnose OSA (apnoea-hypopnoea index (AHI) of >5).Pulse oximetry is a useful screening test but may miss mild and moderate OSA.Polysomnography is the definitive method of sleep study. [1]
Stridor
Occurs during wakefulness. May be relevant history of tumour, inhaled foreign body, neck surgery causing laryngeal nerve injury, or retro-pharyngeal abscess.
Laryngoscopy: may reveal source of upper airways obstruction.
Sleep-related groaning (catathrenia)
Rare. Expiratory vocalisation during sleep that has a different vocal quality from expiratory snoring.
Sleep studies with special sound recording device: allows differentiation of snoring from other types of noise.

Social anxiety disorder

Phobias
Excessive or unrealistic fear of specific objects or situations, rather than fears of being negatively evaluated or embarrassed. Anxiety is cued by anticipated or actual exposure to the phobic stimuli.
Structured clinical interview.
Panic disorder
Individuals with panic disorder (with or without agoraphobia) tend to experience high anticipatory anxiety across a range of situations; may experience recurrent, unexpected panic attacks in the absence of any phobic cues; and interpret their intense physical symptoms as threatening or dangerous. Focus of the fear is on the consequences of the panic sensations.
Structured clinical interview.
Generalised anxiety disorder (GAD)
Anxiety is more diffuse in nature, characterised by pervasive worry across several domains, such as health, relationships, finances, and job/school. Anxiety is not specifically cued by social situations or fears of negative evaluation.
Structured clinical interview.
Post-traumatic stress disorder (PTSD)
Onset follows a potentially life-threatening stressor. Additional differential symptoms include emotional numbing and re-experiencing the trauma.
Structured clinical interview.
Separation anxiety disorder
Anxiety sensations are cued by perceived and actual separation from family members, rather than fears of being negatively evaluated or criticised by others.
Structured clinical interview.
Avoidant personality disorder (APD)
Pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. APD may also be distinguished by non-social avoidance, including avoidance of novel situations and positive affect. [31] About 36% of social anxiety cases are comorbid with APD, leading some authors to argue that APD is a more extreme and severe version of generalised social anxiety disorder. [32] [33]
Structured clinical interview.
Substance abuse
Panic and anxiety sensations are caused by the direct physiological effects of substance abuse or as a result of substance withdrawal.
Urine and blood testing for illicit substances.
Hyperthyroidism
Patients may have unexplained weight loss, palpitations, tremor, muscle weakness, or unexplained protrusion of the eyes.
Serum TSH is low in hyperthyroidism.
Alcohol abuse
Alcohol-induced symptoms show onset with alcohol use and offset after the alcohol has been metabolised.
Urine and blood alcohol testing.

Soft-tissue sarcoma

Lipoma
Soft, often subcutaneous masses. Mobile on palpation; size change unusual; usually <5 cm.
Usually simple structure on imaging; PET scan cold.
Gastrointestinal ulcer
May be clinically indistinguishable from GISTs.
No mass seen on CT/MRI scan.
Lymphoma
Nodal disease is often associated with non-Hodgkin's lymphoma and is unusual in sarcomas.
Histology staging investigations from biopsy can differentiate.
Metastatic carcinoma
Hx of primary-site tumour; weight loss; older age.
Histology staging investigations from biopsy can differentiate.
Neuroma
Change in size or pain related to size change.
Positive emission tomography imaging; MRI to define local invasion.

Spinal cord compression

Transverse myelitis
Approximately one third of patients report a febrile illness preceding the symptoms. Most have leg weakness of varying degrees of severity. The arms are involved in a minority of cases.Associated illnesses include multiple sclerosis, rheumatoid arthritis, HIV infection, and sarcoidosis.
CSF analysis shows pleocytosis with a modest number of lymphocytes and increase in total protein.MRI shows focal demyelination with possible enhancement at the appropriate level. Lyme titres are occasionally found to be high. [35]
Guillain-Barre syndrome (GBS)
Two-thirds have a history of gastroenteritis or influenza-like illness weeks before onset of neurological symptoms. It is frequently severe and presents with features which are similar to those of spinal cord compression, as an ascending paralysis initially with weakness in the legs that spreads to the upper limbs and the face, along with complete loss of deep tendon reflexes. Autonomic signs may be present in some variations. May develop progressive respiratory muscle weakness requiring ventilation.
Typical CSF findings include albumin-cytological dissociation, that is, an elevated protein level (1-10 g/L or 100-1000 mg/dL) without an accompanying increased cell count. A sustained increased WBC count may indicate an alternative diagnosis such as infection.Electrodiagnostics (EMG and nerve conduction studies) may show prolonged distal latencies, conduction slowing, conduction block, and temporal dispersion of compound action potential in demyelinating cases. In primary axonal damage, the findings include reduced amplitude of the action potentials without conduction slowing. [36]Nearly 40% of patients are seropositive for Campylobacter jejuni. [37]
HIV-related myelopathy
History of HIV infection or high-risk behaviours (IV drug use, HIV-infected blood transfusion, unprotected sex).Signs and symptoms referable to the spinal cord lesions, including paraparesis, often accompanied by spasticity or ataxia (or both) coupled with dementia.
ELISA testing should be ordered when HIV testing is indicated. False-negatives may occur during window period immediately after infection and before antibodies to HIV have developed. A positive result should be confirmed with a Western blot or second ELISA. The window period can be reduced to 2 to 4 weeks by using fourth-generation tests and those that include IgM antibodies to HIV.CSF, microbiological, and spinal imaging studies may be inconclusive or non-specific. [38] [39]
Amyotrophic lateral sclerosis (ALS)
Presents as a combination of upper motor neuron (UMN) and lower motor neuron (LMN) symptoms and signs.Approximately 60% of ALS patients experience muscle weakness and stiffness as the initial symptoms. The neurological examination usually shows evidence of muscle weakness (localised or widespread, depending on the extent of the disease). The examination also reveals muscle atrophy. The muscles may be so stiff that, when the neurologist moves them, they continue to move abnormally afterwards. When the neurologist tests the knee jerk reaction, the movement is abnormally quick (hyper-reflexia).
EMG testing is a significant part of the diagnosis. The current criteria define a positive EMG when signs of active denervation include fibrillation potentials and positive sharp waves, with fasciculation potentials. [40]
Multiple sclerosis
Can mimic clinical symptoms of spinal cord compression. However, in almost all cases of multiple sclerosis there are also brain lesions.Has a variable presentation with multiple episodes separated by space (i.e., neurological symptoms result from lesions in different CNS sites) and time. Common symptoms include progressive limb weakness, gait difficulty, ataxia, loss of balance, and paroxysmal vertigo.In the setting of acute paraparesis, visual symptoms (visual loss) may be present. This is neuromyelitis optica (NMO). NMO is thought to be a distinct entity from MS by many neurologists. It has a relapsing course (80% to 90%), and predominantly affects females. [41]
Brain MRI typically shows areas of demyelination.CSF examination shows raised IgG and oligoclonal banding.If NMO suspected (optic neuritis, myelitis, longitudinal cord lesion on MRI), NMO-IgG seropositivity. [41]
Diabetic neuropathy
History of diabetes mellitus. Pain and loss of sensation in the feet in a glove-and-stocking distribution. Bladder dysfunction may be present due to autonomic neuropathy.
Nerve conduction studies show reduction in sensory nerve conduction velocity and a decrease in amplitude.
Polymyositis
Symmetrical weakness of shoulder and pelvic girdles.
Elevated muscle enzyme levels (e.g., CK), often with a positive ANA titre.Characteristic changes in EMG include increased needle insertional activity, spontaneous fibrillations, low-amplitude short-duration poly-phasic motor potentials, and complex repetitive discharges.Diagnosis is confirmed with muscle biopsy, indicating immune cell infiltration and destruction of muscle fibres.
Hereditary muscular dystrophy
Severe proximal and distal muscle weakness without sensory changes from an early age.
MRI and EMG/nerve conduction studies will show only myopathic changes and no spinal cord compression.
Peripheral neuropathy
Peripheral neuropathy and neuropathies due to diabetes or thyroid disease may be difficult to differentiate from neurological symptoms of compression neuropathies.
Nerve conduction studies and EMG are helpful in confirming neuropathy and characterising the neuropathy, that is, demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy.

Spinal stenosis

Peripheral vascular disease
An important differential diagnosis is claudication from vascular insufficiency, as both conditions tend to affect older patients. Leg pain of vascular claudication is usually cramping, begins distally, and progresses proximally. Patients with vascular insufficiency will not report improvement of symptoms with lumbar flexion. Patients with vascular claudication will have more difficulty walking uphill due to increased demand for oxygen, while those with spinal stenosis often find it easier, since they flex forwards when walking uphill.Peripheral circulation should be evaluated in patients with decreased pedal pulses, trophic skin changes, or any other sign of arterial insufficiency.
MRI typically does not show radiographical signs of lumbar stenosis.Lower limb duplex ultrasonography and angiography will confirm vascular insufficiency.
Lumbosacral intervertebral disc herniation
Disc herniations generally cause unilateral radiculopathy (i.e. pain and numbness in a specific dermatome, occasionally weakness in a muscle group) rather than neurogenic claudication. Onset is generally acute. Straight leg raise is often positive. Disc herniation is generally more common in younger patients (30 to 60 years old).
MRI shows paracentral, lateral, or foraminal disc herniation with no, or insignificant, narrowing of the spinal canal.
Spinal compression fracture
With thoracolumbar compression fracture, pain usually occurs in the mid or upper back. Patients give history of trauma, prolonged steroid use, or osteoporosis in older population (pathological osteoporotic fracture).Neurogenic claudication does not occur unless there is retropulsion of fracture fragments at the level of the cauda equina. Rarely do patients develop thoracic radiculopathy or myelopathy from retropulsion of fracture fragments at the level of the spinal cord.
Plain x-rays, CT, or MRI demonstrate fracture.
Metastatic disease of the spine
May be a history of prostate, breast, lung, kidney, thyroid, or other malignancy and/or unexplained weight loss. Back pain is often the predominant symptom and is usually worse at night. Patients often are unable to find a position of comfort. Pain from metastatic disease may be out of proportion to the usual back pain associated with degenerative changes.Back pain and neurological symptoms are present for a relatively short duration (days to a few months). Neurological symptoms are more common than in lumbar stenosis and may include significant muscle weakness, paraplegia, and bladder and bowel dysfunction.
Plain x-rays, CT, or MRI show vertebral body and/or pedicle disruption at one or more spinal levels.
Vertebral osteomyelitis or discitis
High-risk patients include intravenous drug users, patients on haemodialysis, and those with diabetes. More common in immunosuppressed patients and those with HIV, in whom a skin infection or UTI may lead to spinal osteomyelitis. Patient should be asked about history of recent infection and weight loss.Neurological deficits can occur if an epidural abscess develops, but neurogenic claudication does not. Back pain is the predominant symptom.
Plain x-rays reveal loss of disc space and erosion of cortical end plate margins.MRI of the involved vertebral body and disc space shows hypointensity in T1 signal and hyperintensity in T2 signal. Affected areas enhance with gadolinium contrast.WBC count, C-reactive protein levels, and erythrocyte sedimentation rate may be elevated.Blood cultures are positive in less than 50% of patients.CT-guided biopsy is the diagnostic study of choice.
Primary spinal, intradural, or intramedullary tumour
Primary spinal tumours are rare. Pain from intramedullary tumours is worse at night or when the patient is lying down (compression from venous stasis), and conservative treatment fails to relieve the pain.Neurological symptoms from cord or cauda equina compression are more common than in patients with spinal stenosis.
Plain x-rays, CT, or MRI show evidence of the tumour.
Ankylosing spondylitis
Usually seen in men and in younger patients (onset at age 30 to 40 years). Causes morning back stiffness, hip pain and swelling (caused by large joint arthritis). It is not relieved with rest and improves with exercise.
Plain x-rays, CT, or MRI show the classic picture of a 'bamboo spine' (i.e., multi-level spinal fusion). Sacroiliac joints may be obliterated on plain x-rays.Test for HLA-B27 antigen is positive.
Trochanteric bursitis and degenerative arthritis of the hip
Pain radiates to the lateral aspect of the thigh in about 20% to 40% (pseudoradiculopathy) but rarely extends to the posterior thigh or below the knee. Numbness and paraesthesiae are not dermatomal in distribution. Walking may trigger pain but, unlike in neurogenic claudication, pain is also triggered when the patient lies on the affected side. Symptoms are often unilateral. With trochanteric bursitis, there is significant localised tenderness over the greater trochanter, and Patrick's test is positive (external rotation of the hip increases pain).
Plain x-rays, CT, or MRI may show signs of hip arthropathy in the absence of evidence of significant lumbar stenosis. MRI may also demonstrate inflammatory changes along the trochanteric region.
Diabetic neuropathy
History of long-standing diabetes. Pain in the feet is in a non-dermatomal, stocking distribution. The pain is described as burning, constant, and not related to activity. The sole of the foot is usually tender to pressure from the examiner's thumb. Bladder dysfunction might be present because of autonomic neuropathy.
EMG shows characteristic findings of multiple axonal sensory mononeuropathies.
Epidural abscess
Presentation can be non-specific. Fever, malaise, and back pain are the most consistent early symptoms. May be local tenderness, with or without neurological deficit. Abscess can develop from contiguous spread from osteodiscitis, haematogenous spread, or from direct inoculation from injection, surgery, or penetrating trauma.
MRI with gadolinium contrast demonstrates epidural abscess.WBC, ESR, and CRP may be elevated.Blood cultures may be positive.
Degenerative disc/facet joint pain
In the abscence of stenosis, degenerative changes affecting the disc and facet joint can cause back pain that radiates to the buttocks and posterior thighs. Flexion exacerbates pain from a degenerative disc, while extension aggravates facet joint symptoms. Pain is mechanical rather than claudicatory or radicular.
Plain radiographs show loss of disc height and degenerative changes.MRI shows loss of disc hydration and height and facet joint degeneration without neural element compression.

Spina bifida and neural tube defects

Spine segmental dysgenesis
A sporadic disorder characterised by congenital acute-angle kyphosis or kyphoscoliosis that is localised to a spinal segment, usually in the thoracolumbar or upper lumbar spine. [63]The spine is normal above and below the affected area and neurological impairment is due to congenital hypoplasia or absence of roots at the segment rather than to cord tethering.
Plain x-rays will show vertebral anomalies such as hemivertebrae.MRI spine documents the specific spine and cord pathology such as vertebrae fusions or hemivertebrae, split cord, nerve malpositions, and low-lying cord.
Caudal regression syndrome (sacral agenesis)
A rare disorder associated with maternal diabetes that affects the sacral or lumbosacral spine.Patients typically have sparing of sensation and characteristic sacral anomalies.
Plain x-rays and MRI spine will show the characteristic bony defects.
Multiple vertebral segmentation disorder
Autosomal recessive disorder characterised by short trunk dwarfism, multiple segmentation anomalies of the vertebral column, and costal anomalies.
Plain x-rays and MRI spine identify the dystrophic vertebrae, and/or multiple fused vertebrae, kyphosis, split cord, syrinx, and dystrophic cord.
VACTERL (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheo-oesophageal fistula and/or oesophageal atresia, renal agenesis, and dysplasia and limb defects)
A non-random association of multiple mid-line congenital anomalies including vertebral, anal, and cardiac defects, tracheo-oesophageal fistula, renal anomalies, and limb anomalies.
Plain x-rays will show bony defects.Barium enema identifies fistulas and imperforate anus.Echocardiography reveals cardiac anomalies.Renal ultrasound will identify hydronephrosis and associated renal anomalies.MRI identifies characteristic spine and cord malformations.

Spontaneous bacterial peritonitis

Secondary peritonitis
Much rarer than spontaneous bacterial peritonitis (SBP) as a cause of infected ascitic fluid. It may be suspected if there is no history of liver disease or malignancy.Typically not the large-volume distention seen with ascites caused by liver disease or malignancy and therefore associated with SBP.Secondary peritonitis may cause more rigidity.
Polymicrobial growth on ascitic fluid culture, which is particularly suggestive of secondary peritonitis if there is an anaerobic or fungal organism.Ascitic fluid is more likely to have increased protein and lactate dehydrogenase with reduced glucose. [56]Ascitic fluid is more likely to have increased carcinoembryonic antigen and alkaline phosphatase. [57]There is less likely to be a decreased absolute neutrophil count on repeat paracentesis. [58]
Tuberculous peritonitis
There may be extra-abdominal signs and symptoms of tuberculosis (pleural, pulmonary, CNS, bony, genitourinary). Abdominal symptoms may be similar to those of SBP.
The definitive test is peritoneal biopsy with examination for granulomas.Acid-fast staining of ascitic fluid is not a good differentiator, because it is negative in up to 92% of patients with peritoneal tuberculosis. [59]CT scan may show enlarged abdominal lymph nodes.Adenosine deaminase level >39 units/L is highly suggestive of peritoneal tuberculosis. [60]
Intraperitoneal haemorrhage into ascitic fluid
Signs of haemorrhagic shock may be present. A history of a recent large-volume paracentesis may be a clue to haemorrhage. Abdominal pain and distention may be similar to SBP.
The presence of grossly bloody ascitic fluid on paracentesis, especially if prior paracentesis did not demonstrate haemorrhagic ascites, is suggestive of intraperitoneal haemorrhage.
Pancreatic ascites
There may be a history of previous pancreatitis. Abdominal symptoms and signs may be difficult to differentiate from SBP.
Peritoneal fluid absolute neutrophil count likely to be normal.Amylase is typically elevated (>1000 units/L), and the ratio of ascitic fluid amylase to serum amylase is approximately 6. [61]In a case series of 8 patients with pancreatic ascites, ascitic fluid amylase values ranged from 280 to 5730 units/L. [62]The serum albumin-ascites albumin gradient (SAAG) is usually <11 g/L (<1.1 g/dL), whereas in SBP (which typically occurs in the patient with portal hypertension), SAAG is >11 g/L (>1.1 g/dL).CT scan may demonstrate a pancreatic pseudocyst.

Sporotrichosis

Primary cutaneous nocardiosis
Painful skin lesions; may be associated with regional lymphadenopathy and mild systemic symptoms.
Demonstration of modified acid-fast organisms on skin lesion smears; culture of skin lesion drainage or biopsy material positive for Nocardia brasiliensis. [19]
Cutaneous Mycobacterium marinum infection
Similar signs and symptoms, although lesions may occasionally be tender; hx of acquisition from freshwater or salt water. [19]
Demonstration of acid-fast organisms on skin lesion smears; culture of skin lesion drainage or biopsy material at 32°C (89.6°F) on Lowenstein-Jensen media.
Cutaneous leishmaniasis
No differentiating signs/symptoms from lymphocutaneous sporotrichosis. [19] Less-nodular lymphangitic spread with old world leishmaniasis.
PCR or culture from ulcerative lesions positive for Leishmania.
Ulceroglandular tularaemia
Painful ulcers accompanied by tender regional lymphadenopathy and severe constitutional symptoms; hx of contact with infected rabbits or bites from infected arthropods in endemic areas of the northern hemisphere. [19] Short (<1 week) incubation period.
Serological testing positive for Francisella tularensis.

Squamous cell carcinoma of the skin

Actinic keratoses
Appear as red scaly papules or plaques that may be pruritic or tender.The extent of hyperkeratosis varies, and retention of compact keratin layers may result in the formation of a cutaneous horn.
Biopsy will show basal layer keratinocyte atypia that does not involve the full thickness of the epidermis.
Basal cell carcinoma
Presents as pearly papules or plaques with rolled borders and telangiectasias.
Biopsy shows tumour nests with basaloid differentiation with large nuclei and scant cytoplasm. Significant keratinocyte atypia or mitotic figures are not found.
Seborrhoeic keratosis
Tends to appear 'stuck on' with a waxy or scaly appearance.
Biopsy shows proliferation of keratinocytes without atypia, often with pseudohorn cysts.
Common warts
Black dots may be visible upon paring.
Biopsy may show viral cytopathic changes in the superficial spinous and granular layers. Keratinocyte atypia is rare.
Prurigo nodularis
A 'picker's nodule' is a benign lesion caused by chronic rubbing, scratching, or picking.
Biopsy shows irregular acanthosis of the epidermis and a thickened granular layer. No keratinocyte atypia is present.
Amelanotic melanoma
A lesion that has little or no colour or may appear red, pink, or scar-like white.It has an asymmetrical shape and an irregular, faintly pigmented border.Always considered in a differential of a changing or growing neoplasm.
Biopsy shows a melanocytic neoplasm.

ST-elevation myocardial infarction

Unstable angina
Clinical presentation may not differentiate.
ECG may show non-specific ST-segment and T-wave changes.Cardiac biomarkers are normal.
Non-ST-elevation myocardial infarction
Clinical presentation may not differentiate.
ECG may show non-specific ST-segment and T-wave changes, but does not show ST-segment elevation.Cardiac biomarkers are elevated in both non-ST-elevation MI and STEMI.
Aortic dissection
Patients typically present with tearing chest pain, notably between the shoulder blades.They can be in considerable distress and haemodynamically unstable.Peripheral pulses may be unequal or absent distally.
CXR may show a widened mediastinum.ECG may be unremarkable, show sinus tachycardia, or show ST-segment changes if the dissection extends proximally and involves the coronary ostium.A CT of chest and abdomen with IV contrast showing the presence of a dissection flap and a true lumen and false lumen is diagnostic for aortic dissection.A trans-oesophageal echocardiogram may also show the dissection flap with the true and false lumens.
Pulmonary embolism
Patients classically present with acute onset of sharp stabbing chest pain that is pleuritic in nature and associated with SOB.A background of increased clotting tendency, such as known inheritable thrombophilia or connective tissue disease; known deep venous thrombosis (DVT); or previous PE increases the likelihood of the diagnosis.Other risk factors include recent prolonged immobilisation and limb trauma.
Patients are hypoxic with an increased arterial-alveolar gradient on the arterial blood gas.ECG may show sinus tachycardia or right ventricular strain with prominent S wave in lead I, prominent Q in lead III, and flipped T in lead III (S1Q3T3), or can be unremarkable.D-dimer is useful for screening. A negative d-dimer excludes PE; if positive, further work-up is required to confirm PE.V/Q scan of the lungs will show a mis-match between ventilation and perfusion images. A high-probability scan confirms PE and a normal scan excludes PE. Indeterminate scans need further work-up if indicated by the clinical picture.Spiral CT scanning of the chest with contrast will show a filling defect in the pulmonary artery if a blood clot is present.Pulmonary angiography is the test of choice to show thrombus in the pulmonary artery; however, it is an invasive study and is uncommonly used.
Pneumothorax
Patients present with sudden onset of pleuritic chest discomfort and SOB.Tachycardia, hypotension, and cyanosis suggest a tension pneumothorax.Known underlying medical conditions that predispose to pneumothorax, such as chronic obstructive pulmonary disease, connective tissue disease, or recent chest trauma, may support this diagnosis.
CXR shows a visceral pleural line.
Pneumonia
Patients usually have an insidious onset of fevers, cough (that may be productive of sputum), and SOB.Chest discomfort may be pleuritic in nature.Examination will usually confirm pneumonic consolidation with decreased resonance, decreased air entry, and rales over the affected lung.
WBC count is usually elevated with neutrophilia.CXR shows increased alveolar markings.Blood and sputum cultures may be positive for an infective organism.
Pericarditis
Patients can present with chest pain of varying quality that is typically better on sitting up and leaning forwards and worse with lying down.There may be a history of recent viral syndrome and a pericardial friction rub on clinical examination.
ECG may have diffuse ST-segment elevation that is concave up ('saddle-shaped') with PR segment depression. [16]Cardiac biomarkers can be elevated if inflammation extends into the myocardium.Inflammatory markers such as CRP and ESR may be elevated.CXR demonstrating a globular cardiac shadow is suggestive.Echocardiogram may show a pericardial effusion or may be unremarkable.
Myocarditis
Patients often have a recent history of influenza-like illness or underlying autoimmune condition such as SLE.They are likely to be young and often do not have risk factors for CAD.Myocarditis is more likely to present with symptoms of cardiac failure than with chest pain.
ECG changes and cardiac biomarkers can mimic MI.Inflammatory markers (ESR and CRP) and autoimmune assays may be elevated.Test of choice is endomyocardial biopsy.
Gastro-oesophageal reflux disease
Patients present with burning retrosternal discomfort that is relieved by antacids.
Diagnosis is usually clinical.Cardiac biomarkers, ECG, and CXR are normal.Oesophagogastroduodenoscopy (OGD) is indicated for patients with persistent or atypical symptoms and may show oesophagitis (erosions, ulcerations, strictures) or Barrett's oesophagus.
Oesophageal spasm
Patients present with squeezing retrosternal discomfort that may be relieved by glyceryl trinitrate (due to relaxation of the spasm).
Cardiac biomarkers, ECG, and CXR are normal.Oesophageal manometry or barium swallow may show evidence of dysmotility.
Costochondritis
Musculoskeletal chest wall discomfort that is worse with certain movement and deep breaths.Focal tenderness over the costochondral joints may be present.
Cardiac biomarkers, ECG, and CXR are normal.
Anxiety or panic attack
Normal examination; however, evidence of hyperventilation is usually present.
Cardiac biomarkers, ECG, and CXR are all normal.

Stable ischaemic heart disease

Aortic dissection
The pain of aortic dissection is typically severe, sudden in onset, and often described as tearing, sharp, or stabbing. The pain may be retrosternal, interscapular, abdominal, in the neck, lower back, or lower extremities. Hypertension is common with distal aortic dissections. Pulse deficits are common, particularly in proximal dissections. [50]
Chest radiograph may show a widened mediastinum, leading to initial suspicion.Contrast-enhanced CT or transoesophageal echocardiogram will demonstrate the presence of a true and false lumen with dissection flap. [50]
Pericarditis
The pain of acute pericarditis is typically severe, sudden in onset, and retrosternal or left precordial in location. The chest pain is often pleuritic, aggravated by supine positioning and relieved by sitting upright. A pericardial friction rub may be appreciated on examination. [51]
ECG will show diffuse ST-segment elevation and PR-segment depression. [51]
Pulmonary embolism
Dyspnoea is the most common symptom of acute pulmonary embolus. History may reveal symptoms of lower extremity venous thrombosis (erythema, warmth, pain, or swelling). Tachypnoea and tachycardia are the most common signs. [52]
D-dimer: normal value is useful to rule out pulmonary embolism in patients with low clinical probability of pulmonary embolism. [52]An ECG is useful to exclude alternate diagnosis.Non-specific findings seen with pulmonary embolism include ST abnormalities, T-wave changes, and right or left axis deviation.
Pneumothorax
Typically, presents with acute chest pain, dyspnoea, and cough. Examination reveals decreased breath sounds and hyperresonance over the area of pneumothorax. [53]
The chest radiograph will show a visceral pleural line at the apex in an upright film; caution is advised in interpretation of supine films. [53]
Pneumonia with pleurisy
Pleurisy results in localised chest pain that is worsened by deep breathing. [54]In the setting of pneumonia, patients will commonly complain of dyspnoea, fevers, cough, and sputum production.On examination, bronchial breath sounds and dullness to percussion may be appreciated in focal lung region.
A pulmonary infiltrate with or without an effusion is typically seen on chest radiograph.
Oesophagitis
Dysphagia and odynophagia are the predominant complaints of oesophagitis.Infectious oesophagitis typically occurs in immunocompromised patients. [55]Medications should be reviewed for common offenders of pill-induced oesophagitis. [56]History of radiation therapy may raise suspicion for radiation oesophagitis.
The results of barium swallow and endoscopy are dependent on the cause of oesophagitis.Candida albicans will appear as a shaggy mucosa on barium swallow and numerous small white-yellow plaques on endoscopy.HSV appears as small ulcers on barium swallow and EGD, whereas large, deep, and linear ulcers suggest CMV. [55]In suspected pill oesophagitis, endoscopy may be indicated to exclude infectious causes. [56]Barium swallow and endoscopy can demonstrate the severity of mucosal damage with radiation oesophagitis.
Oesophageal spasm
Patients may complain of intermittent chest pain and dysphagia in the setting of oesophageal spasm. Glyceryl trinitrate can improve oesophageal spasm by inducing smooth muscle relaxation. [57] This can make oesophageal spasm difficult to differentiate from angina.
Barium swallow may show prominent non-propulsive contractions leading to a corkscrew appearance.Oesophageal manometry may demonstrate repetitive and aperistaltic contractions. [57]
GORD
Oesophageal reflux typically presents as an epigastric or retrosternal burning pain, with radiation toward the throat. Patients may report resolution of the pain with a trial of antacids. [58]
Typically managed empirically with acid-suppressive therapy. Oesophageal pH monitoring can be performed to demonstrate episodes in which the oesophageal pH drops to below 4. [58]
Biliary colic
The pain of biliary colic is localised to the RUQ, occurring 15 to 30 minutes after a meal and persisting for 3 to 4 hours. It is often associated with nausea, vomiting, and bloating. [59] [60] [61]
Ultrasound or hepatobiliary iminodiacetic acid scan will reveal gallstones. [59]
Cholecystitis
Similar to the pain of biliary colic, the pain of cholecystitis is localised to the RUQ and is often associated with nausea and vomiting. Unlike biliary colic, patients with cholecystitis also have fever, abdominal tenderness, and leukocytosis. [60]
Ultrasound will demonstrate gallstones and/or thickening of the gallbladder wall. Hepatobiliary iminodiacetic acid scan will not fill the gallbladder due to obstruction of the cystic duct. [60]
Choledocholithiasis
Similar to the pain of biliary colic, the pain of choledocholithiasis is localised to the RUQ and is often associated with nausea and vomiting. [61]
Ultrasound generally shows dilated bile ducts and occasionally identifies a biliary stone. Endoscopic retrograde cholangiopancreatography is the gold standard for the diagnosis of common bile duct stones and can be helpful in relieving the biliary obstruction. [61]
Cholangitis
Similar to the pain of choledocholithiasis, the pain of cholangitis is localised to the RUQ and is often associated with nausea and vomiting. Unlike choledocholithiasis, patients with cholangitis typically present with fever and jaundice in addition to abdominal pain. [60] [61]
Ultrasound generally shows dilated bile ducts and occasionally identifies a biliary stone. Endoscopic retrograde cholangiopancreatography is the most sensitive and specific test for the diagnosis of common bile duct stones and can be helpful in relieving the biliary obstruction. [60] [61]
Peptic ulcer disease
Recurrent episodes of pain in the epigastrium with radiation to the back are common in peptic ulcer disease. The pain may temporarily improve with ingestion of food. [62]
Oesophagoduodenoscopy: visualisation of an ulceration in the gastric or duodenal mucosa. [62]
Pancreatitis, acute
The pain of pancreatitis is located in the epigastrium and commonly radiates to the midback. It is constant, lasting for hours to days, and not relieved by vomiting or bowel movements. A history of alcohol use or gallstones may provide a specific cause. Abdominal examination varies with the severity of the attack. [63]
The diagnosis is most supported by an elevation in serum amylase and lipase 3 times the upper limit of normal. Ultrasound is useful to evaluate for cholelithiasis, while CT is useful to evaluate the extent of pancreatic inflammation or findings suggestive of pancreatic necrosis. [63]
Costochondritis
The pain of costochondritis is typically localised to one or more of the costochondral or costosternal junctions, with reproduction of the pain on palpation.
Diagnosed solely on reproduction of the pain with palpation of the tender areas.
Fibromyalgia
Tender points of fibromyalgia can be located to near the sternum along the second intercostal space. Additionally, patients may complain of fatigue and chest heaviness. Patients with fibromyalgia will typically have multiple additional tender points localised to the neck, buttocks, shoulders, arms, and the upper back. [64]
Diagnosis is on clinical grounds by identifying point tenderness areas (typically, patients will have at least 11 of the 18 classic tender points) with no accompanying tissue swelling or inflammation, and by excluding other medical conditions as a cause. [64]
Rib fracture
Rib fractures are often preceded by a history of traumatic injury to the area and pain is often localised to the area of fracture.
Chest radiograph may show rib fractures. Pain with palpation of the tender area also suggests the diagnosis.
Sternoclavicular arthritis
The pain of sternoclavicular arthritis is usually maximal immediately over the sternoclavicular joint. A history of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis should raise suspicion for this diagnosis. [65]
Diagnosis is usually on clinical grounds as the joint is poorly visualised by conventional radiography. [65]
Herpes zoster virus infection
The majority of patients with herpes zoster will have a prodromal pain in the dermatome that will become affected. Before the development of vesicles, it can be difficult to differentiate this chest pain from other causes of chest pain. [66]
Dermatomal distribution and presence of vesicular skin lesions. [66]
Anxiety disorders and panic attacks
The increased tension and autonomic hyperactivity of anxiety disorders and panic attacks may lead to feelings of fatigue, muscle aches, palpitations, and chest pain that may lead to concern of heart disease. [67] [68]
Diagnosis is on clinical grounds.

Standard-Risk ALL

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Status epilepticus

Psychogenic non-epileptic status epilepticus (SE)
Defined as prolonged or repeated episodes of psychogenic non-epileptic seizures.May present as violent motor events mimicking generalised convulsive SE (more common) or subtle unresponsive events mimicking non-convulsive SE (less common).Physical signs that may favour psychogenic non-epileptic SE are persistent eye closure, variable degree of responsiveness, asynchronous and discontinuous motor activity, pelvic thrusting, absence of postictal state, and prolonged attack duration. A prior psychiatric history also favours the diagnosis of psychogenic non-epileptic SE.
The only method to differentiate epileptic from non-epileptic SE is video-EEG. Video-EEG recording of a psychogenic non-epileptic event will be normal.
Delirium
This acute state of cognitive and perceptual decline can mimic non-convulsive SE. In its broader definition, it may include all states of altered awareness or confusion that are commonly referred to as encephalopathy.Encephalopathy may be secondary to metabolic, toxic, or infectious causes.
Distinction between non-convulsive SE and encephalopathy may be a challenging task, even for a well-trained epileptologist. EEG patterns are often confusing, especially in the case of metabolic encephalopathies such as hepatic or renal.Laboratory findings such as high liver aminotransferases or ammonia in conjunction with clinical and EEG judgement may help in reaching the correct diagnosis.Performing EEGs on patients with acute mental changes is strongly recommended.
Coma
Defined as a state of absent cognitive and motor responsiveness.Non-convulsive SE can be mistakenly diagnosed as coma. [8] The distinction is crucial, since coma is usually irreversible, whereas non-convulsive SE is often treatable.
EEG may be very helpful in distinguishing coma from non-convulsive SE. However, certain periodic EEG patterns can be difficult to differentiate from ictal patterns. Such EEG patterns are commonly seen in hepatic or post-anoxic coma.Performing EEGs on all patients with a presumed diagnosis of coma is highly recommended.

Stevens-Johnson syndrome and toxic epidermal necrolysis

Drug hypersensitivity syndrome
Presents with fever, rash, lymphadenopathy, arthralgias, hepatitis, nephritis, carditis, eosinophilia, and atypical lymphocytes. [5]Most frequent causative agents are phenytoin, phenobarbital and carbamazepine, and the sulphonamides. [5] [54]More frequent among black people.It takes 2 to 6 weeks from beginning the drug therapy to onset of rash. [6]
Skin biopsy and clinical presentation; FBC may show eosinophilia; LFTs may be elevated if hepatitis present.
Staphylococcal scalded skin syndrome
Disease of infancy or early childhood (Ritter's disease).The bacteria produce two toxins, ETA and ETB, which disrupt the epidermal granular cell layers through interdesmosomal splitting but without epidermal necrosis and with few inflammatory cells. [4] [55]
FBC, blood and wound cultures, and skin biopsy.
Toxic shock syndrome
Either Staphylococcus or Streptococcus can be the origin of the infection, presenting with signs of sepsis and a sunburn-like rash.
FBC, blood and wound cultures, and skin biopsy.
Graft versus host disease
Patients develop a rash, but the skin in graft versus host disease does not slough off as readily as it does in Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).Patients who have been transplanted develop a rash as a result of rejection rather than a drug-induced reaction. Ocular lesions are rare. [4]
FBC and skin biopsy.
Vesicant/blister agent poisoning
Clinical effects such as erythema and blisters will occur immediately with phosgene oxime or lewisite or be delayed for 2 to 24 hours with mustard gas. [56]
Skin biopsy.
Erythema multiforme
Target lesions normally triggered by herpes viruses. [6] [7]
Skin biopsy.
Burns, skin
Result of trauma with destruction of the epidermis and dermis to variable degrees. [5]
Skin biopsy if there is not a good history.
Paraneoplastic pemphigus
Blistering disease with a malignant comorbidity. [5]
Skin biopsy.

Stomach cancer

Peptic ulcer disease
Evidence of GI bleeding, weight loss, early satiety, a palpable mass or lymphadenopathy, jaundice, progressive dysphagia, recurrent vomiting, FHx of cancer, or onset of symptoms after age 55 increases the likelihood of cancer. [26]
Distinguished from gastric neoplasm by endoscopy and biopsy. All peptic ulcers should have repeat endoscopy after treatment to document healing.
Benign oesophageal stricture
May have a hx of gastro-oesophageal reflux disease.
Distinguished from gastric neoplasm by endoscopy and biopsy.
Achalasia
Suspect malignancy in patients with symptoms for <6 months, presentation after age 60, and excessive weight loss relative to the duration of symptoms. [27]
Distinguished from gastric neoplasm by manometry, endoscopy, and biopsy.Pseudoachalasia is the term for features of achalasia (based on barium esophagography, managraphy, and endoscopy findings) that are ultimately shown to be due to malignancy.

Strabismus

Pseudostrabismus
Facial features (e.g., epicanthal folds, wide nasal bridge, eyelid abnormalities) may falsely convey the impression of ocular misalignment.This is most common in young children and in the Asian population.
Hirschberg test: shows centred corneal light reflexes in the absence of true manifest strabismus.Cover test: negative.Uncover test: negative.
Blurred vision
Some patients complain of double vision when in fact the vision is actually not clear.
Blurred vision persists when one eye is covered.In contrast, the double vision caused by strabismus is binocular (present only when both eyes are open).
Monocular diplopia
Refractive errors; may cause a 'ghost image'.
Monocular diplopia persists when one eye is covered.In contrast, the double vision caused by strabismus is binocular (present only when both eyes are open).Symptoms corrected with spectacles or contact lenses.
Convergence insufficiency
Patients complain of eye strain after reading or near work.
On examination there is large exophoria (latent outward deviation) when looking at near objects, and decreased amplitudes of fusional convergence.Convergence insufficiency is the only disorder that responds to treatment with orthoptic exercises.

Strongyloides infection

Hookworm
No differentiating signs or symptoms.Hookworm has a finite life span of <5 years. Thus, in people residing in a developed country for 5 years or more, strongyloides is the more likely diagnosis as it carries on lifelong auto-infection within the human body without need for re-exposure.
In stool specimens having delayed processing time, hookworm ova may hatch with larvae that appear similar to strongyloides larvae. Therefore it is important to determine whether a delay in processing occurred. Repeat testing may be necessary.Hookworm therapy is insufficient to eradicate strongyloides.Eosinophilia, when present, is a marker of treatment failure.
Schistosomiasis
More likely in people emigrating from Africa.
Dipstick U/A may be positive for blood in urinary schistosomiasis.Standard stool or urine ova and parasite (O&P) examination will differentiate the conditions, although it is a relatively insensitive test for diagnosis of schistosomiasis.Serological testing is available and may differentiate the conditions.
Filariasis
May be no differentiating signs or symptoms.More likely to cause dermatitis and nodules.Loa loa more likely to present with visual defects and signs of eye infection.
Forms part of the differential diagnosis of unexplained eosinophilia.Giemsa-stained blood smear examination and serological testing are used primarily for diagnosis.Microfiliariae identified on peripheral blood smear (a late-night sample increases detection rates).
Amoebiasis
No differentiating signs or symptoms.
Identification of amoeba in stool samples.Unlike strongyloides infection, Entamoeba histolytica and Entamoeba dispar do not cause eosinophilia.
Asthma
Both conditions may result in cough and wheeze and may at times be asymptomatic.Asthma less likely to present with abdominal or skin features.Strongyloides infection more likely in a person migrating from an endemic area.
Stool O&P examination and serology are negative.The presence of eosinophilia in a high-risk person (such as a person migrating from an endemic area) alerts the physician to look for other causes apart from asthma, especially when the asthma-like symptoms are of new onset in an adult.
Irritable bowel disease
Both conditions may cause abdominal pain and altered bowel habit.Strongyloides infection more likely in a person migrating from an endemic area.
Eosinophilia not present.
Somatisation disorder
May be no differentiating features.Strongyloides infection more likely in a person migrating from an endemic area.
Eosinophilia not present.
Psychogenic pruritus
Less likely to present with non-dermatological symptoms and signs although there may be no differentiating features.Strongyloides infection more likely in a person migrating from an endemic area.
Eosinophilia not present.
Urticaria
Urticarial lesions resolve within 24 hours.
Clinical diagnosis.

Stye and chalazion

Blepharitis
History generally reveals bilateral ocular burning, itching, foreign body sensation, photophobia, crusting on the eyelids, and redness of lid margins. In severe cases, corneal changes can occur, leading to reduced vision.With associated dry eye syndrome, patients may report sensation of eye dryness.With associated acne rosacea, facial erythema, facial telangiectasia, papules, and pustules are seen.With associated seborrhoeic dermatitis, flaking and greasy skin on the scalp, retro-auricular area, glabella, and nasolabial folds is typical.Chalazion may be associated with underlying blepharitis.
Slit lamp examination is required to confirm the diagnosis and exclude other causes.In atypical unilateral cases, lid biopsy may be warranted to exclude other disorders, in particular malignancies such as basal cell, squamous cell, or sebaceous cell carcinoma.
Dacryocystitis
Obstruction and bacterial infection of the lacrimal sac; easily identifiable on examination as a very tender, swollen, and fluctuant mass below the medial epicanthus. [1]More common in children, typically preceded by a viral upper respiratory infection, and commonly associated with constitutional symptoms. [1]Palpation of the sac may express pus from the lacrimal puncta. [3] [1]
If suspected, CT scanning of the face and orbits may be useful to identify inflammation of the lacrimal system and to exclude orbital cellulitis.
Dacryoadenitis
Bacterial infection of the lacrimal gland caused by viral or bacterial infections; patients usually complain of constitutional symptoms.Typically presents with pain and swelling at the lateral border of the superior lid, with tearing and discharge from the eye. [3] [1]
If suspected, CT scanning of the face and orbits may be useful to identify inflammation of the lacrimal gland and to exclude orbital cellulitis.
Peri-orbital cellulitis
Typically results from secondary bacterial infections as a result of local skin trauma, spread from impetigo, or extension from sinusitis. Sometimes associated with fever. Patients have more diffuse swelling, oedema, and erythema of the lid and peri-orbital region. [1] [3]
CT scanning of the face or orbits may be useful to exclude orbital cellulitis.
Orbital cellulitis
Often initially presents with signs and symptoms of peri-orbital cellulitis.Additionally patients complain of eye pain with movement, decreased vision, fever, and headache.On examination they may display marked chemosis with proptosis and elevations of intra-ocular pressure. [3] [1]
CT scanning typically performed to identify extension of disease and exclude the potential of abscess formation.
Sebaceous and squamous cell carcinoma
Might be suspected in older patients with lesions of the eyelids that persist.
For suspicious lesions, biopsy to exclude carcinoma is warranted.

Subacute granulomatous thyroiditis

Graves' disease
Thyroid is non-tender or minimally tender compared with the extremely tender gland with subacute granulomatous thyroiditis.May have extrathyroidal manifestations, such as ophthalmopathy or pretibial myxoedema (thyroid dermopathy).
Radioactive iodine uptake: high (>30%).Radioiodine thyroid scan: diffuse uptake in an enlarged goitre.ESR: normal.TSH receptor antibodies: positive.
Infectious, suppurative, or acute thyroiditis
Pharyngeal abscess is usually present, with dysphagia as a prominent symptom.Unlike in subacute granulomatous thyroiditis, there may be skin erythema over the painful thyroid.
White blood cell count: elevated.FNA biopsy: polymorphonuclear neutrophils. Gram stain shows organisms (bacteria, fungal hyphae). [19]
Toxic multinodular goitre
Goitre generally is non-tender. Thyroid gland contains multiple nodules.
TFTs: mildly to moderately elevated.ESR: normal.Radioactive iodine uptake: mildly elevated.Radioiodine thyroid scan: multiple areas of increased and decreased uptake in nodules within an enlarged thyroid.
Lymphocytic (silent) thyroiditis
Absence of pain, symptoms of thyrotoxicosis, diffuse goitre.
Radioactive iodine uptake may be variable: low, normal, or high.ESR: normal.Antithyroid antibodies: positive.FNA biopsy (rarely required): lymphocytic infiltrate.
Painful Hashimoto's (chronic lymphocytic) thyroiditis
Symptoms of hypothyroidism. In rare cases may be associated with pain. [20]
Radioactive iodine uptake: very low.Antithyroid antibodies: positive.FNA biopsy: lymphocytic infiltrate with varying degrees of fibrosis.
Thyroid cancer
Anaplastic carcinoma may cause thyroid pain if rapidly growing. Firm to hard thyroid texture.
TFTs: normal.Radioactive iodine uptake: normal.Radioiodine thyroid scan: area deficient in iodine uptake.Thyroid ultrasound: discrete mass.
Haemorrhage into a goitre or nodule
Focal pain over the thyroid nodule. May be clinically indistinguishable from subacute granulomatous thyroiditis.
Radioactive iodine uptake: normal.Radioiodine thyroid scan: area deficient in iodine uptake.Thyroid ultrasound: discrete thyroid nodule with cystic degeneration.
Globus hystericus in the presence of goitre
Thyroid is non-tender and soft.
TFTs: normal.Radioactive iodine uptake: normal.Radioiodine thyroid scan: isotope distribution that is typical of a nodular goitre.
Exogenous thyroid hormone excess
Either factitious or due to meat contamination by animal thyroid. [21]
Radioactive iodine uptake: low or no uptake.Thyroid ultrasound: normal.

Subarachnoid haemorrhage

Non-aneurysmal perimesencephalic SAH
There are no features in the history or on examination that differentiate this condition from aneurysmal SAH.
No aneurysms are found on angiography. CT usually reveals subarachnoid blood in front and around the pons (perimesencephalic or pontine cistern). Caution is required when this blood distribution pattern is seen, as it may also be seen with a ruptured aneurysm located in the posterior circulation. [43] Overall, it has a better outcome than aneurysmal SAH.
Arterial dissection
Pain is less severe and is frequently felt behind the eye or localised to anterior or posterior neck region. Dull neck pain might precede a more severe pain, occurring at the time of SAH. Examination findings might include a Horner’s sign and/or neurological deficits related to stroke secondary to dissection.
Dissected arteries are visualised on cerebral angiography, MRA, or CTA. Axial T1 and T2 fat-suppressed neck MRI images might visualise the characteristic intramural haemorrhage associated with dissection.
Cerebral and cervical arteriovenous malformation (AVM)
Symptoms and signs are similar to aneurysmal SAH. Subarachnoid haemorrhage could be preceded or accompanied by findings related to mass effect caused by the AVM.
Arteriovenous malformations visualised on cerebral angiography, MRA, or CTA.
Dural arteriovenous fistulae (AVF)
Symptoms and signs are similar to aneurysmal SAH.
Arteriovenous fistulae visualised on cerebral angiography, MRA, or CTA.
Vasculitis
A subacute to chronic history of recurrent neurological deficits, with corresponding abnormalities on examination. Headache is usually less severe.
Cerebrospinal fluid pleocytosis may be present. Angiography might disclose beading of medium and small intracranial arteries. Brain and meningeal biopsy is, however, the diagnostic standard for this condition.
Saccular aneurysms of spinal arteries
Pain localised to posterior neck/occipital area. Meningismus might be more prominent. A sciatica-like picture due to blood in the lumbar thecal sac can be seen.
Spinal angiography visualises the aneurysm(s).
Cardiac myxoma
Age between 30 and 60 years. Cardiac, obstructive, or constitutional symptoms precede SAH.
Echocardiography is method of choice for diagnosis.
Septic (mycotic) aneurysm
On physical examination there may be a fever, heart murmur, skin petechiae, Osler's nodes, Janeway lesions, splinter haemorrhages under the nails, and Roth spots in optic fundi. Ischaemia may occur in the bowel and spleen.
Subarachnoid blood is usually focal, not widely distributed in cisterns, fissures, and sulci as in aneurysmal SAH. Blood cultures may be positive. Blood tests may show an elevated ESR and peripheral leukocytosis. Cerebral angiography reveals aneurysms located distally, typically in the distribution of the middle cerebral artery (MCA). Intracerebral haematomas are likely to be seen on CT. Echocardiography might reveal valvular vegetations.
Pituitary apoplexy
Patients have a known history of pituitary adenoma. Visual loss is seen in up to half of patients with pituitary apoplexy (not a feature of aneurysmal SAH). Acute adrenal insufficiency develops in two-thirds of patients.
MRI with contrast shows pituitary haemorrhage or infarction. Subarachnoid blood is minimal and confined to the region around the pituitary gland.
Cocaine abuse
There is a history of drug abuse preceding the event. The headache is usually less severe.
Urine drug screen is positive for cocaine. Subarachnoid blood is usually minimal and focal in sulci. CT might also reveal intracerebral haematomas.
Anticoagulants
There is a history of anticoagulant use. The headache is less severe.
A CT shows minimal subarachnoid blood and possible intracerebral haematomas. Coagulation studies are abnormal (prolonged PTT and/or elevated INR).
Sickle cell disease
There is a history of sickle cell disease, previous strokes, or sickling episodes.
Computed angiography might reveal intracerebral haematomas associated with subarachnoid blood. Haemoglobin S is identified upon testing.

Subdural haematoma

Epidural haematoma
'Lucid interval', younger patients, usually an associated skull fracture.
CT of the brain shows lenticular shape that does not cross suture lines.
Intracerebral haematoma
There may be no differences in symptoms and signs.
CT of the brain.
Diffuse axonal injury (DAI)
History of trauma involving shear or acceleration/deceleration force; high-grade DAI typically results in coma.
CT of the brain, MRI of the brain with gradient recalled echo.
Stroke
Fall may be involved, sudden onset of deficit before the fall, may have history of atrial fibrillation or cardiac arrhythmia, or history of prothrombotic disorder.
CT of the brain, MRI of the brain with diffusion and perfusion-weighted imaging, magnetic resonance angiography.
Seizure
After postictal state, patient typically returns to baseline. There may be Todd paralysis.
CT of the brain, EEG.
Substance abuse
There may be no differences in symptoms and signs, although there may be no history of trauma.
Toxicology screen may be useful in differentiating causes of altered mental status.

Sudden infant death syndrome

Non-accidental trauma or abusive injury, including Munchausen's syndrome by proxy
Signs of trauma, including bruising in unusual places, rib fractures, spiral fractures of long bones, and retinal haemorrhages.Recurrent episodes of cyanosis, apnoea, or apparent life-threatening event.Previous history of unexplained infant deaths in siblings.Recurrent medical visits for unusual and/or multiple different symptoms for which definitive causes are not found or for which carer's concerns exceed clinical findings.
Radiographic and ophthalmological examinations are helpful, but are not necessarily diagnostic.Presence of intra-abdominal injuries (e.g., liver/hollow viscous injuries).Autopsy often unable to distinguish intentional from accidental suffocation. [81] [82]
Gastro-oesophageal reflux
Clinically obvious reflux.Coughing, choking, and cyanosis after feeds, especially when placed flat.Failure to thrive.
Clinical diagnosis.Chronic respiratory effects may be identified on PFTs, or by bronchoscopy with or without bronchial alveolar lavage.Biopsy/histology may be carried out at post-mortem evaluation.
Respiratory syncytial virus
Upper respiratory symptoms of cough and nasal congestion.Apnoea, which may be the only presenting symptom.Contact with an infected individual
Can be rapidly tested for via nasal swab (culture or ELISA-based).
Pertussis
Upper respiratory symptoms of cough and nasal congestion.Apnoea, which may be the only presenting symptom.Contact with an infected individual.
Can be rapidly tested for via nasal swab (culture or ELISA-based).
Inborn errors of metabolism (especially fatty oxidation disorders, mitochondrial disorders, and urea cycle defects)
Failure to thrive/poor feeding.Persistent vomiting.Lethargy.Altered mental state: may be acute or sub-acute onset.History of a sibling with similar metabolic disorder or prior unexplained death.
Serum and urine tests: particularly acylcarnitine profile, serum ammonia and amino acid concentrations, and urine organic acids concentrations. Results are disorder-specific.Specific genetic enzyme assays as clinically indicated. Results are disorder-specific.Muscle biopsy for histology. Confirmatory for mitochondrial disorders. Histological changes are disorder-specific.

Suicide risk management

Self-harm
Self-inflicted injury that is not associated with an implicit or explicit intent to die.Examples of self-harm behaviours include burning/cutting after an emotionally upsetting event or burning/cutting as a method of manipulation or threat.
Clinical diagnosis.

Sunburn

Polymorphous light eruption (PMLE)
Classically presents with pruritic papules, plaques, vesicles, or erythema, occurring after the first sun exposure of the season.Usually appears 1 to 4 days after UV exposure but can sometimes be seen within minutes. The skin typically demonstrates 'hardening' (diminishing signs and symptoms) with subsequent UV exposure. [10]
Clinical differentiation is usually sufficient given the pattern of onset and the polymorphous nature of lesions, although bullous PMLE eruptions may be confused with acute sunburn.A substantial percentage of those affected may have negative photo-testing results. [10]Skin biopsy reveals prominent papillary dermal oedema with a lymphocytic perivascular infiltrate.
Photo-toxic dermatitis
Caused by a systemic or topical photo-sensitiser that, coupled with sunlight, creates a markedly increased sunburn reaction. [10]Systemic medications associated with photo-toxicity include amiodarone, doxycycline, griseofulvin, NSAIDs, and fluoroquinolones, among others. [12]Furocoumarin is a topical photo-sensitiser found in a variety of plants, including citrus fruits, figs, celery, and parsley, among others (phytophotodermatitis).Bergapten, the photo-toxic ingredient in oil of bergamot, is found in many fragrances (berloque dermatitis).Onset within hours; no prior sensitisation is required.Induced by radiation in UVA range.UVA, unlike UVB, can penetrate window glass.
Clinical differentiation is usually possible, especially in cases due to external photo-sensitisers, which typically demonstrate a patchy or linear distribution.When the diagnosis is in doubt, photo-testing may be performed, which shows erythema at lower than expected doses in the UVA range. [12]Skin biopsy is generally not helpful, as histological findings may be difficult to distinguish from acute sunburn.
Photo-allergic dermatitis
Typically presents as a pruritic, scaly erythematous eruption in a photo-distribution.May be associated with external or internal triggers, resulting in photo-allergic contact dermatitis or photo-allergic drug reaction, respectively.Photo-allergic reactions have been associated with the common sunscreen ingredient oxybenzone, as well as oral drugs, including thiazides, sulphonamides, sulphonylureas, and phenothiazines. [12]Occurs only in previously sensitised individuals and may have delayed onset of up to 14 days. [10]
Clinical differentiation is usually sufficient, given the predominant symptom of itching and typical eczematous appearance.The diagnosis can be confirmed by photo-patch testing, showing a positive reaction on the irradiated side only. [12]Skin biopsy demonstrates histological features similar to allergic contact dermatitis, including spongiosis and a dermal lymphohistiocytic infiltrate.
UV recall reaction
Occurs in areas of prior sunburn or UV photo-therapy after the administration of chemotherapy or antibiotics (most notably methotrexate).Recall reactions may not appear for days to weeks or, in some cases, years after exposure to inciting medication. [20]May have similar presentation with erythema and vesicles/bullae.
Clinical differentiation is usually sufficient, as UV recall and enhancement reactions are not associated with acute sun exposure.Skin biopsy reveals apoptotic keratinocytes similar to sunburn.
SLE
Classic malar erythema ('butterfly rash') often following sun exposure.Can also present in other, typically photo-distributed areas.Duration varies from hours to weeks.Often poikilodermatous (pigmentary/atrophic changes and mottled appearance) with occasional papules and scale. [12]Other cutaneous and systemic symptoms typically allow for clinical differentiation.
Clinical differentiation is usually sufficient.Skin biopsy demonstrates a lichenoid reaction pattern characterised by colloid bodies, vacuolar changes in basal keratinocytes, a thickened basement membrane, perivascular and periadnexal lymphocytic infiltrates, and dermal deposition of acid mucopolysaccharide. Immunofluorescence studies may reveal granular deposits of C3, IgG, and IgM at the dermal-epidermal junction.

Superficial thrombophlebitis

Deep vein thrombosis
Acute onset of swelling, warmth, redness, and pain that is more diffuse and can involve the whole leg. Palpable cord is not common along the course of affected vein unless there is concomitant superficial thrombophlebitis (SVT).
Doppler ultrasound (DUS): thrombus in the deep venous system will confirm diagnosis.
Cellulitis
Erythema is usually localised and confluent and associated with tenderness and generalised swelling. There may be associated lymphangitis or tender lymphadenopathy, which is not characteristic of SVT. A palpable cord is not present with cellulitis. Systemic findings of fever, chill, and myalgias are more common with cellulitis.
DUS: compressible veins, absence of superficial vein thrombus.
Lymphoedema
Usually chronic rather than acute non-pitting oedema of the extremity and involving the digits. Oedema does not resolve or improve with recumbency.
DUS: compressible veins, absence of superficial vein thrombus; B-mode imaging shows subcutaneous oedema.
Chronic venous insufficiency
Usually chronic leg swelling with associated ectatic veins, varicose veins, and skin changes that may include hyperpigmentation, stasis dermatitis, panniculitis, lipodermatosclerosis, and venous ulcers.
Diagnosis usually made on clinical examination.Confirmation on DUS: can show valvular incompetence and chronic venous obstruction.
Erythema nodosum
Most common form of panniculitis, usually consisting of raised painful bilateral tender lesions that are frequently located over both shins. There is no palpable cord.
Skin biopsy: septal panniculitis.
Cutaneous polyarteritis nodosum
A form of vasculitis consisting of nodules of a bright red to blue colour that follow the course of arteries. Usually bilateral and become confluent to form painful subcutaneous plaques.
Skin biopsy: necrotising vasculitis of the arteries.
Insect stings or bites
Swelling and redness usually extend over a large area and do not follow the course of a vein. There may be associated pruritus.
Diagnosis usually made on clinical examination.DUS: negative for superficial vein thrombus.
Tendonitis
Usually pain, mild swelling, and warmth in the area of a tendon (Achilles' heel, patellar). Pain increases with movement of affected joint, and a tendon friction rub may be palpable. Pain worse during and after activity, and the tendon and joint area can become stiff as the swelling impinges on the movement of the joint.
Ultrasound: thickened, blurred tendon, and possible hypo-echoic foci within tendon.MRI: tendon injury.
Lymphangitis
Erythema, warmth, and tenderness along the course of a lymphatic vessel from source of infection (e.g., cellulitis) to regional lymph nodes. Lymph nodes usually palpable.
DUS: compressible veins, absence of superficial vein thrombus.

Superior vena cava syndrome

Cardiac tamponade
Absence of facial and upper-extremity oedema.Variation of jugular venous pressure (JVP) with respiration (prominent x-descent).Pulsus paradoxus present.
Pericardial effusion is seen on CT chest.Echocardiography shows bouncing septum, marked respiratory variation in the early left ventricular filling velocity (>25%), and right ventricular diastolic collapse.
Constrictive pericarditis
Elevated JVP with prominent negative descents (x- and y-descent).Presence of Kussmaul's sign (increase in JVP with inspiration).
Echocardiography may show thickened pericardium and marked respiratory variation in the early left ventricular filling velocity (>25%).MRI is the investigation of choice, as it shows pericardial thickening and ventricular interdependence.Cardiac catheterisation shows discordance of left and right ventricular pressures with respiration, which has high specificity for diagnosis.
Acute COPD exacerbation
Extensive bilateral expiratory wheezing, hypoxia, and hypercarbia.
Peak flow, spirometry, and bronchodilator response help in differentiating.Presence of obstructive defect on pulmonary function testing is seen.
Right-sided heart failure
Preserved respiratory variation in JVP, prominent negative descents, and sometimes increased v wave due to tricuspid regurgitation.
Echocardiography will show right ventricular dysfunction and dilated inferior vena cava with lack of inspiratory collapse.
Pulmonary embolism
Upper-extremity oedema is usually absent.
CT chest with contrast will show presence of thrombus inside the pulmonary artery.
Cardiac tumour
Upper-extremity oedema is usually absent.
Echocardiography or cardiac MRI will show presence of a mass, usually inside the right side of the heart.

Sustained ventricular tachycardias

Supraventricular tachycardia (SVT) with aberration
None.
ECG, electrophysiological (EP) study: failure to meet criteria for ventricular tachycardia (VT); absence of fusion or capture beats; absence of AV dissociation.
SVT with pre-excitation
None.
ECG, EP study: failure to meet criteria for VT; absence of fusion or capture beats; absence of AV dissociation.
Electrical artifact
None.
Evidence of underlying sinus rhythm on ECG discernible through electrical noise (motion artifact).Evidence of arrhythmia isolated to specific leads on 12-lead ECG (tremor).
Sepsis or fever
Raised temperature, malaise, rigors, symptoms of underlying infection.
ECG shows underlying sinus rhythm.Appropriate cultures may show presence of infecting agent.
Panic/hyperventilation
Anxiety or panic, fear of imminent death, paraesthesiae, chest pain, numbness , faintness, dizziness, sweating.
ECG shows underlying sinus rhythm.Hospital Anxiety and Depression Scale (HADS) anxiety score >11.
Hyperthyroidism
Tremor, anxiety, weight loss but good appetite, diarrhoea, eyelid retraction and lid lag, fatigue, heat intolerance, goitre.
ECG shows underlying sinus rhythm.Raised T4/T3 and low TSH levels.
Acute haemorrhage
Low BP, abdominal pain with haematemesis and/or melaena, haemorrhage from other sites, hx of likely cause of blood loss: for example, trauma or post-operative.
ECG shows underlying sinus rhythm.US or CT may show internal problem and/or collection of blood.
Phaeochromocytoma
Headache, sweating, palpitations, fluctuating HTN, anxiety, nausea, vomiting, weight loss, heat intolerance, tremors, chest and abdominal pain.
ECG shows underlying sinus rhythm.Increased plasma and 24-hour urine epinephrine (adrenaline)/norepinephrine (noradrenaline)/metanephrine levels.Glucagon stimulation test positive.Clonidine suppression test positive.CT, MRI, or m-iodobenzylguanidine (MIBG) scans show tumour in adrenal gland.
Pericarditis
Tachycardia and friction rub; jugular venous distension and pulsus paradoxus indicate effusion causing tamponade.
ECG shows diffuse concave-up ST-elevation, associated PR depression.CXR may show enlarged cardiac silhouette (globular heart) if pericardial effusion present.Echocardiogram may show pericardial effusion.
Caffeine, alcohol, amphetamine use
Hx of recent use or high intake.Tremor, agitation, signs of intoxication.
ECG shows underlying sinus rhythm.

Syndrome of inappropriate antidiuretic hormone

Pseudohyponatraemia
Many patients are asymptomatic. Symptoms, if present, depend on the nature and severity of the underlying cause.Possible symptoms or signs of poorly controlled diabetes (polyuria, polydipsia) may be present if hyperglycaemia is the cause.Eruptive xanthoma may be seen in patients with severe hyperlipidaemia.Patients with hyperproteinaemia may show signs of multiple myeloma or other rarer causes.
Suspicion is raised if measurement of serum glucose, lipids, and protein reveals one of these to be elevated.Elevated serum glucose: diagnosis is confirmed if calculation of the corrected serum sodium value reveals a normal sodium level. The equation for SI units is: corrected sodium (mmol/L) = measured sodium (mmol/L) + 0.016{(glucose [mmol/L] x 18)-100}. The equation for conventional units is: corrected sodium (mEq/L) = measured sodium (mEq/L) + 0.016 [glucose (mg/dL) - 100].Elevated serum lipid level, particularly triglyceride: normal serum osmolarity confirms diagnosis.Elevated serum protein, particularly, globulin (multiple myeloma): normal serum osmolarity confirms diagnosis.
Hypovolaemia
History of poor oral intake, vomiting, diarrhoea, or diuretic use help to distinguish hypovolaemia from SIADH.Evidence of dry mucous membranes, skin tenting, and flat neck veins can accompany hypovolaemia, although clinical assessment is poor at predicting volume status. [10]
Central venous pressure (CVP) <8.Urine sodium <20 mmol/L (20 mEq/L).Elevation in serum sodium with a diagnostic trial of 1 to 2 L of normal saline infusion.
Cerebral salt-wasting
There is a history of intracranial bleed or trauma.
Volume depletion (CVP <8) with a urine Na >120 mmol/L (120 mEq/L). [11]Fractional excretion of urea <30%. [12]Continued high urine sodium despite hypertonic saline or water restriction.
Hypervolaemia (e.g., CHF, cirrhosis, pregnancy)
Dyspnoea, pulmonary oedema, elevated jugular venous pressure, ascites, lower extremity oedema.
CVP elevated.Urine sodium <40 mmol/L (40 mEq/L).
Psychogenic polydipsia
There may be a psychiatric history or excess fluid intake elicited during history.
Urine osmolality <100 mmol/kg H2O (<100 mOsm/kg H2O).24-hour urine osmoles >600 mmol (mOsm >600 mOsm).
Poor solute intake (e.g., beer potomania, low-protein diet)
Beer drinking or malnourished patients with poor dietary solute intake and high water intake. Low solute excretion limits water excretion causing water retention.
Urine osmolality <100 mmol/kg H2O (<100 mOsm/kg H2O).24-hour urine osmoles <300 mmol (<300 mOsm).
Renal failure
Hypertension; oedema may be present.
Elevated creatinine.
Addison's disease
Pigmentation of skin and mucosa, weight loss, hypotension.
Low cortisol levels.Responds to steroid administration.
Hypothyroidism
Dry coarse skin, myxoedema, hair loss, weight gain.
High TSH and low serum thyroid hormone levels.Responds to treatment with thyroid hormone.

Syphilis infection

Genital herpes
There may be a preceding history of fever, genital blisters or sores, and lymphadenopathy with first episode herpes simplex.The patient may describe previous episodes.On physical examination there are typically multiple, painful vesicular or ulcerative lesions on or around the genitals or rectum.
Isolation of HSV in cell culture confirms the diagnosis, although the sensitivity is low, and decreases as the ulcers heal.Viral culture isolates will identify if HSV-1 or HSV-2 is causative. [3]Increasingly, PCR is being used to diagnose and type HSV.
Chancroid
Characterised by painful genital ulcers and painful inguinal lymphadenopathy. Lesions of primary syphilis are typically not painful.Usually occurs in discrete outbreaks.On physical examination there may be an erythematous papule, pustule or painful ulcer, as well as painful uni-lateral inguinal lymphadenopathy (bubo formation), which may rupture.
Haemophilus ducreyi is identified on specialist culture medium, which is not widely commercially available and has a sensitivity of less than 80%. [49]PCR testing is up to 100% sensitive but is not universally approved. [50] [49]Therefore a positive diagnosis of chancroid is suggested by the presence of painful genital ulcers with no evidence of syphilis or HSV. [3]
Primary HIV infection
Not preceded by genital ulceration.However, genital ulceration may be present at the same time as primary HIV infection and the rash associated with the ulceration.
Laboratory tests positive for HIV, including antigen (P24 antigen) tests.
Other acute viral exanthemas
Not preceded by genital ulceration.
Laboratory tests positive for specific virus.
Scabies
Usually pruritic.Typical distribution: inter-digital, wrists, nipples, ankles, buttocks.
Diagnosis is usually clinical, but skin scrapings and microscopy for Sarcoptes scabiei may be performed.
Eczema
Typical clinical appearances.Usually sparing palms and plantar aspects of feet.Not associated with signs of systemic infection.
Diagnosis is usually clinical.Skin biopsy can be undertaken to confirm diagnosis.
Psoriasis
Typical clinical appearances.Usually sparing palms and plantar aspects of feet.Not associated with signs of systemic infection.
Diagnosis is usually clinical.Skin biopsy can be undertaken to confirm diagnosis.
Lichen planus
Typical clinical appearances.Usually sparing palms and plantar aspect of feet.Not associated with signs of systemic infection.
Diagnosis is usually clinical.Skin biopsy can be undertaken to confirm diagnosis.
Genital warts
Pink lumps, in genital and/or peri-anal skin and mucous membranes. Not necessarily confined to opposing membranes.Not associated with other signs of secondary syphilis (rash, constitutional symptoms, generalised lymphadenopathy).
Diagnosis is usually clinical.Negative syphilis serology.
Alzheimer's dementia
Progressive dementia.No specific differentiating symptoms and signs.Less likely to have a history of possible signs and symptoms of earlier stages of infection.
Exclusion of syphilis (negative syphilis serology).
Vascular dementia
Progressive dementia.Multi-infarct dementia often associated with other evidence of arteriopathy.Less likely to have a history of possible signs and symptoms of earlier stages of infection.
Exclusion of syphilis (negative syphilis serology).

Systemic candidiasis

Bacterial sepsis
No differentiating signs/symptoms between fungal and bacterial causes of sepsis.
Blood culture positive for bacterial pathogen.
Drug-induced fever
History of a causative drug use.
Diagnosis is clinical and no specific tests are available. Discontinuation of the suspected drug should cause the fever to abate.
Pulmonary embolism
Patients may present with pleuritic chest pain, dyspnoea, hypoxia, and hypotension.
CT pulmonary angiogram shows a filling defect in the pulmonary arteries.

Systemic lupus erythematosus

Rheumatoid arthritis (RA)
May be difficult to differentiate clinically.Patients with SLE frequently present with an inflammatory arthritis with a similar pattern to RA, although it tends to be less symmetrical.
Joint x-rays demonstrate symmetrical, erosive arthritis.
Antiphospholipid syndrome
Characterised by the occurrence of venous or arterial thrombosis or recurrent fetal loss in the presence of antiphospholipid antibodies.
Antiphospholipid antibodies: anticardiolipin antibodies IgG or IgM present in moderate or high levels on ≥2 occasions at least 6 weeks apart and lupus anticoagulant detected on ≥2 occasions at least 6 weeks apart. These antibodies may also be positive in SLE.10% of patients with antiphospholipid syndrome are b-glycoprotein positive. [61]Venereal Disease Research Laboratory (VDRL) test: false-positive result.
Systemic sclerosis
Raynaud's phenomenon is present in almost all patients with systemic sclerosis, being the initial symptom in about 70% of patients. Patients with SLE often have Raynaud's phenomenon as well, but these tend not to ulcerate compared to patients with systemic sclerosis.Patients with systemic sclerosis have characteristic sclerodactyly and calcinosis, not present in SLE.
Auto-antibodies: positive anti-centromere antibodies (limited cutaneous systemic sclerosis) or anti-topoisomerase 1 (Scl-70) antibodies (diffuse cutaneous systemic sclerosis).
Mixed connective tissue disease (MCTD)
MCTD is characterised by a combination of manifestations similar to those in SLE, systemic sclerosis, and myositis. Difficult to differentiate clinically.
Auto-antibodies: positive anti-RNP antibodies are specific to MCTD.Patients with MCTD tend to lack other antibodies such as anti-Sm, anti-Ro, anti-La, and anti-dsDNA.
Adult Still's disease
A variant of juvenile rheumatoid arthritis characterised by seronegative chronic polyarthritis in association with a systemic inflammatory illness, which manifests as symptoms similar to those of SLE.The fever in adult Still's disease usually occurs once or twice daily with marked temperature elevation and normal temperature in between.The rash is often only seen during febrile periods and is a salmon-coloured macular or maculopapular non-pruritic lesion.
Elevated ferritin has been reported in most patients. Ferritin should therefore be checked in patients presenting with such symptoms and, if elevated, lead to a suspicion of adult Still's disease.Joint symptoms are similar to RA and joint erosions and fusion on x-ray may occur, unlike in SLE.
Lyme disease
May be difficult to distinguish clinically.History of possible erythema migrans or exposure to ticks.
Lyme-specific IgM and IgG are positive.Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
HIV
May be difficult to distinguish clinically.History of exposure to risk factors for HIV.
Serum HIV ELISA test is positive.Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
CMV
May be difficult to distinguish clinically.May be asymptomatic.
CMV serology is positive for infection.Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
Infectious mononucleosis
May be difficult to distinguish clinically.
Positive agglutination test, for example, monospot.Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
Haematological malignancy
SLE may be difficult to distinguish clinically from haematological malignancy.
Bone marrow, other histology or imaging tests may distinguish the diagnosis.Auto-antibodies will be negative.
Glomerulonephritis
Difficult to differentiate clinically if no other symptoms or signs associated with SLE are present, for example, Raynaud's, rash.
Antibodies for dsDNA may be positive if SLE is the cause.Renal biopsy may aid in diagnosis.
Chronic fatigue syndrome
No other signs that are typically associated with SLE (e.g., Raynaud's, rash) will be present
Auto-antibodies will be negative.
Generalised tonic-clonic seizures
May be difficult to differentiate clinically as seizures can be a feature of SLE. However, no other signs that are typically associated with SLE (e.g., Raynaud's, rash) will be present.
EEG will demonstrate epileptiform activity.Brain MRI may demonstrate a lesion.Auto-antibodies will be negative in epilepsy.
Fibromyalgia
Poorly localised symmetrical musculoskeletal pain with no diurnal variation.Poorly responsive to analgesics/non-steroidal anti-inflammatory drugs (NSAIDs).May co-exist with SLE.Positive typical tender points.
Diagnosis is typically clinical.Auto-antibodies will be negative.
Depression
Typically no systemic manifestations (e.g., rash) unless co-exists with SLE.
Diagnosis is typically clinical.Auto-antibodies will be negative.
Septic arthritis
May be difficult to differentiate clinically if patient presents with monoarthritis and no other features of SLE.
Joint aspiration or synovial biopsy yields positive culture.

Systemic sclerosis (scleroderma)

Primary Raynaud's phenomenon
Tends to have milder symptoms.Attacks are symmetrical and precipitated by cold or emotional stress.There is an absence of digital ulcers.No history or physical signs suggestive of secondary cause.
There are no diagnostic tests for primary Raynaud's phenomenon.
Localised scleroderma (morphea)
Clinical and histopathological skin changes that are indistinguishable from systemic sclerosis.May be in a linear distribution (linear scleroderma).Most often seen in children and young adults, rather than older adults.There is a lack of Raynaud's phenomenon, sclerodactyly, or visceral manifestations.
Abnormal CXR, PFTs, barium swallow make the diagnosis of scleroderma more likely than localised scleroderma (morphea)Diagnosis is clinical.
Mixed connective tissue disease
Patients typically have features of SLE , scleroderma, and polymyositis.
May have testing consistent with features of scleroderma.High titre anti-RNP antibodies usually present.
Eosinophilic fasciitis
Associated with over-exertion.Leads to adherence of skin to underlying fascia, usually sparing the hands and feet.Raynaud's phenomenon is absent.
Peripheral eosinophilia.CXR shows no evidence of interstitial lung disease.PFTs show no evidence of interstitial lung disease or pulmonary artery hypertension associated with scleroderma (PFTs indicate pulmonary hypertension if the diffusing capacity of the lung for carbon monoxide (DLCO) is disproportionately decreased in comparison with the FVC).Negative ANA.Deep biopsy, including the fascia, is important to make the diagnosis. It shows an inflammatory infiltrate with eosinophils.
Scleromyxoedema
Characterised by waxy, yellow-red papules on the head, neck, arms, and upper trunk, occurring over thickened and indurated skin.Associated with a diagnosis of amyloidosis.
Monoclonal spike on serum or urine protein electrophoresis.CXR shows no evidence of interstitial lung disease.PFTs show no evidence of interstitial lung disease or pulmonary artery hypertension associated with scleroderma (PFTs indicate pulmonary hypertension if the DLCO is disproportionately decreased in comparison with the FVC).
Sclerodema (scleroderma diabeticorum)
Most patients also have diabetes.Characterised by skin thickening, affecting the neck, upper back, shoulders, and trunk.Raynaud's phenomenon and internal organ involvement absent.
CXR shows no evidence of interstitial lung disease.PFTs show no evidence of interstitial lung disease or pulmonary artery hypertension associated with scleroderma (PFTs indicate pulmonary hypertension if the DLCO is disproportionately decreased in comparison with the FVC).Negative ANA and anti-topoisomerase I antibody.
Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy
Occurs in patient with renal compromise, usually ESRD. Associated with gadolinium administration.Skin changes may be indistinguishable from scleroderma but Raynaud's phenomenon is usually absent.May have internal organ fibrosis.
CXR shows no evidence of interstitial lung disease.PFTs show no evidence of interstitial lung disease or pulmonary artery hypertension associated with scleroderma. PFTs indicate pulmonary hypertension if the DLCO is disproportionately decreased in comparison with the FVC.Negative ANA and anti-topoisomerase I antibody. Negative anti-RNA polymerase III antibody (there is no correlation with nephrogenic systemic fibrosis and the presence of this auto-antibody).Skin biopsy has distinct pathological findings that distinguish it from scleroderma.
Acrodermatitis chronicum atrophicans
Associated with Borrelia infection.Has a chronically progressive course leading to skin atrophy.Favours the lower extremities and is generally symmetric.
Responds to antibiotics.CXR shows no evidence of interstitial lung disease.PFTs show no evidence of interstitial lung disease or pulmonary artery hypertension associated with scleroderma (PFTs indicate pulmonary hypertension if the DLCO is disproportionately decreased in comparison with the FVC).Negative ANA and anti-topoisomerase I antibody.

Systemic vasculitis

Infective endocarditis
Increased risk if known underlying valvular disease or high-risk behaviour, such as intravenous drug use.
Three paired blood cultures (aerobic and anaerobic) to detect causative organism. Previous antibiotic exposure decreases the yield.Keep blood cultures long enough to exclude HACEK organisms (Haemophilus aphrophilus and Haemophilus paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), although these are not specifically associated with vascular complications.
Hypercoagulability syndromes
Absence of chronic B-type symptoms, such as fevers, weight loss, myalgias, and arthralgias.
Difficult to assess after anticoagulation therapy has started.Heterozygous factor V Leiden and prothrombin mutations (which can be diagnosed through genetic testing) are common and generally not severe enough to mimic vasculitis.It is important to rule out the antiphospholipid antibody syndrome by looking for anticardiolipin antibodies or a prolonged dilute Russell viper venom time (dRVVT).
SLE
Only rarely associated with a true vasculitis, but, as with the primary systemic vasculitides, it can affect multiple organ systems simultaneously.The cutaneous manifestations of SLE, such as a malar rash and discoid lesions, are readily differentiated from the palpable purpura that is found with vasculitis.
Positive anti-nuclear antibody (ANA) test.

T-cell ALL

Acute myeloid leukaemias (AML)
Clinically, ALL and AML may be indistinguishable. Skin infiltration and gum hypertrophy are more common in AML. CNS, testis, and mediastinal involvement are more common in ALL.
In many cases, the leukemic cells of AML or biphenotypic ALL are poorly differentiated with minimal amount of cytoplasm. These cells are difficult to differentiate from those of ALL. [3] [6]In such a case, bone marrow biopsy, peripheral blood smear, cytochemistry, and immunological marker may be helpful in establishing the diagnosis.The presence of myeloid markers and absence of lymphoid ones favour the diagnosis of AML. Scoring panels enable the diagnosis of biphenotypic leukaemia.
Reactive lymphocytosis ('leukemoid reaction')
Infectious mononucleosis may present with thrombocytopenia, fever, malaise, pharyngitis, and, more commonly, lymphadenopathy and splenomegaly. Parvovirus may present with anaemia.
FBC: abnormal lymphocytes; CMV infection and Bordatella pertussis infection may present with significant lymphocytosis. [1] [2]Bone marrow aspiration and biopsy: normal haematopoiesis.Immunophenotyping may show increased numbers of haematogones (normal reactive B-cell progenitors).Epstein-Barr serology: positive.Viral testing: may be positive.Culture of nasopharyngeal secretions: may be positive.
Small-cell lung cancer
History of smoking, cough, hoarseness, dysphagia, haemoptysis, cachexia, and chest pain.Clinical findings of clubbing or Horner's syndrome.
CXR: pulmonary mass.Biopsy: small-cell lung cancer appears histologically as sheets of small round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli. In addition, immunohistochemical staining reveals positivity for chromogranin, neuron-specific enolase, and synaptophysin.
Merkel cell tumour
Skin lesions, local lymphadenopathy, systemic symptoms suggesting dissemination (e.g., pulmonary or neurological symptoms).
Biopsy: the Merkel cell exhibits immunocytochemical properties of both epithelial and neuroendocrine cells. Immunoreactivity for intermediate filaments such as the cytokeratins may differentiate Merkel cell from other undifferentiated tumours.
Rhabdomyosarcoma
Disseminated disease can mimic ALL. May be symptoms and signs suggesting primary site or other symptoms of metastatic disease (e.g., bone pain or respiratory symptoms).
Rhabdomyosarcoma: immunohistochemical staining (IHC) or electron microscopy may provide evidence supporting myogenic differentiation. IHC can detect muscle-specific proteins. [16] [30]
Aplastic anaemia
Aplastic anaemia may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30]Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis.The bone marrow aspiration and biopsy are hypocellular in aplastic anaemia.
Idiopathic thrombocytopenic purpura (ITP)
Childhood ITP may resemble the aleukemic pancytopenic subtype of ALL.
No blast cells in peripheral blood or leucoerythroblastic features. [16] [30] Bone marrow aspiration and peripheral blood smear are helpful in differentiating diagnosis. The bone marrow aspiration and biopsy are normocellular in ITP with preservation of all 3 lineages.

Takayasu's arteritis

Giant cell arteritis (GCA)
Patients are usually older; average age is 74 years. May have polymyalgic syndrome with proximal myalgia. Jaw claudication is common. Lower extremity involvement is less common.
Imaging with CT or MR angiography; GCA is more likely to have cranial artery involvement and less likely to have lower extremity involvement.
Essential hypertension
Intact pulses and the absence of bruits. No marked difference in blood pressure between each side.
Clinical diagnosis.No stenoses on vascular imaging.
Syphilis
Firm, painless ulcer at site of primary inoculation, usually genital region. Symmetrical non-itchy rash accompanies systemic symptoms.
Positive syphilis serology.Catheter or CT angiogram: typical calcification of the proximal ascending aorta.
Tuberculosis (TB)
Persistent productive cough. Recent travel to an endemic area.
Mantoux test: elicits delayed hypersensitivity reaction, which will be positive in people with latent infection, previously cleared infection, or in those previously immunised.CXR: may show evidence of pulmonary TB foci.Sputum culture: takes 4 to 12 weeks to culture acid-fast bacilli but is diagnostic if found.Quantiferon gold test: blood test to detect interferon gamma production when incubated with TB bacilli. Can identify active and latent infection.
Spondyloarthropathy
Back pain and stiffness lasting more than 1 hour, particularly in the mornings. Peripheral arthritis. May be preceded by urethritis or cervicitis in the case of reactive arthritis. Accompanying symptoms may include psoriasis, palmar-plantar pustulosis, iritis, uveitis, or conjunctivitis.
X-ray of spine: may demonstrate sacroilitis.X-ray of peripheral joint affected by arthritis may show periarticular osteolysis in psoriatic arthritis.
Behcet's disease
A triad of oral and genital ulceration with uveitis. Often accompanied by a peripheral arthritis. May have thrombotic arterial and venous occlusions.
Angiography: reveals saccular dilation of involved arteries or thrombotic occlusion.CSF examination supportive but not diagnostic; increased inflammatory cells and protein.
Kawasaki disease
Typically affects children under age 5. High-grade fever with strawberry-tongue-marked lymphadenopathy. Red eyes with uveitis or conjunctivitis. Rash and peeling of the skin on the palms and soles may be seen.
Clinical diagnosis using set criteria.Angiography reveals saccular dilation of coronary arteries if affected.
Marfan's syndrome
Typically tall people with long limbs. May have a family history of Marfan's syndrome. Susceptible to lens dislocation.Systemic signs and symptoms absent.
Clinical diagnosis.Family history.Genetic testing rarely carried out.
Ehlers-Danlos syndrome
May have hypermobile joints or paper-thin skin scars.Systemic signs and symptoms absent.
Angiography: if vascular wall collagen affected, may reveal saccular dilatation of involved arteries.Genetic testing.
Atherosclerosis
More common in men, may have associated risk factors of hypertension, smoking, diabetes, and raised cholesterol. Typically, patients are over age 40.
Angiography: typical abrupt narrowing of artery rather than tapered narrowing. Lesions usually at the vessel origin and carotid bifurcations.
Fibromuscular dysplasia
Pulses present but may be diminished. Hypertension common and most commonly affects renal and carotid arteries.
Angiography: characteristic beading of affected arteries. Aorta not usually involved.

Tapeworm infection

Central nervous system tuberculoma
Patients are normally febrile.There may also be signs of tuberculosis elsewhere (e.g., chronic cough, haemoptysis, bone pain).
Western blot negative.CT and MRI may show ring-enhancing lesions.
Amoebic abscess
Patients are usually febrile with elevated erythrocyte sedimentation rates.
Western blot negative.
Migraine
Patients usually have unilateral motor or sensory signs and headache.
Stool examination and western blot negative.
Epilepsy
Patients usually experience premonitory sensations (fear, epigastric sensation, déjà vu, jamais vu).
Western blot negative.
Gastroenteritis
Patients may be febrile with associated vomiting.
Western blot negative.
Brain tumour
Patients have focal neurological deficits according to location.
Western blot negative.
Liver metastases
Patients may be jaundiced with ascites.
Western blot negative.
Cholecystitis
Patients may have positive Murphy's signs with right shoulder pain.
Western blot negative.
Sarcoidosis
Patients may have erythema nodosum, chronic fatigue, and/or arthralgia.
Western blot negative.
Alcohol abuse
Patients usually demonstrate evidence of alcohol withdrawal including hallucinations and tremor.
Western blot negative.

Temporomandibular joint syndrome

Sinusitis
Sinusitis pain to palpation is localised to the para-nasal and frontal sinuses.TMJ syndrome usually involves the TMJ region and possibly the temporal regions.
Otoscopic examination may reveal an abnormality such as effusion or obstruction.Evaluation is best performed by a dentist when dental pathology is suspected.
Chronic headache
Joint clicking is absent.Pain is not cyclic.
There are no differentiating tests.
Dental pain
Hot/cold testing of teeth indicates extreme sensitivity.Tapping the tooth elicits pain.Joint clicking is absent.
Dental x-rays may reveal peri-apical pathology.Evaluation is best performed by a dentist when dental pathology suspected.
SLE
Clinical manifestations of SLE may be present including malar rash or discoid lupus (thick, red, scaly patches on the skin).Small joints of the hand and wrist are usually affected, although any joint is at risk.Other presenting features include pericarditis, myocarditis, and endocarditis; pulmonary manifestations; autoimmune hepatitis; and glomerulonephritis.
Markers of systemic disease: anaemia, thrombocytopenia, neutropenia, deranged LFTs.Positive antinuclear antibody and anti-extractable nuclear antigen on serological testing.
Rheumatoid arthritis
Patients with rheumatoid arthritis may have other joint involvement, particularly symmetrical small joint polyarthritis in the hands, chiefly affecting the metatarsophalangeal joints and sparing the distal interphalangeal joints.Patients with acute rheumatoid arthritis may also feel generally unwell with fatigue and low mood.
In rheumatoid arthritis, ESR and C-reactive protein (CRP) are abnormal and rheumatoid factor and anticyclic citrullinated (anti-CCP) antibodies are positive.Typical rheumatoid arthritis erosive changes are seen on x-ray, MRI, or ultrasound.
Giant cell arteritis
Patients typically have pain and tenderness over the temporal artery, which may occur with amaurosis fugax and loss of vision.Pain resolves within 3 days of high-dose corticosteroid treatment.
Duplex scanning of temporal arteries may reveal thickening of the arterial wall.Sedimentation rate >100 mm/hour.CRP is usually elevated.Biopsy shows giant cell arteritis.
Neuralgias
Joint clicking is usually absent.Facial pain is elicited by touching a trigger point.
Clinical diagnosis.

Tendinopathy

Rotator cuff tear
Shoulder pain; more common in patients >40 years of age. Focal weakness on examination.
Positive MRI findings.
Osgood-Schlatter's disease
Common cause of knee pain in active youth: boys aged 13 to 14 years old; girls aged 10 to 11 years old. Focal tenderness, swelling, and bump formation over the tibial tubercle.
X-ray: may be normal; often demonstrates enlarged tibial tubercle, sometimes with fragmentation of the apophysis.
Sinding-Larsen-Johansson disease
Knee pain; typically affects younger patients (that is, pre-teen or early teenage) during periods of rapid bone growth. Affects boys more than girls. Focal tenderness to palpation in the inferior pole of the patella on examination.
X-ray: may be normal or may demonstrate calcification at the inferior pole of the patella.
Retrocalcaneal bursitis
Posterior heel pain anterior to the Achilles' tendon, just superior to its insertion. Dorsiflexion aggravates the pain. Positive 2-finger squeeze test on examination. View image
Diagnosis is clinical.
Subcutaneous tendo-Achilles' bursitis (Haglund's deformity or 'pump bump')
Pain in the superficial bursa between the Achilles' tendon and skin, usually caused by ill-fitting shoes with rigid heel backs. Prominence on the lateral aspect of the posterosuperior calcaneus is tender to touch on examination.
Diagnosis is clinical.

Tenosynovitis of the hand and wrist

Osteoarthritis (for de Quervain's; flexor carpi radialis tendovaginitis)
Direct tenderness over corresponding joint. No tenderness over the suspected tendon.
Plain x-rays of affected hand, wrist, and thumb base: arthritic changes including sclerosis, joint space narrowing, osteophytes, and/or cystic changes.
Occult fracture (e.g., scaphoid)
Direct tenderness over corresponding joint. No tenderness over the suspected tendon.
Plain x-ray of affected hand and wrist: occult fracture lines.CT scan and/or MRI if plain x-ray is negative: occult fracture lines.
Cellulitis
Open wound may be present; acute development of signs. Macular erythema with indistinct borders, warmth, tenderness, and oedema.Diagnosis is clinical in most cases.
ESR: elevated.CRP: elevated.Fluid Gram stain/culture: may be positive for causative bacteria.
Septic tendonitis
Open wound may be present; acute development of signs.
FBC with differential: elevated WBC.ESR: elevated.CRP: elevated.Fluid cell count: elevated.Fluid Gram stain/culture: may be positive for causative bacteria.
Septic arthritis
Open wound; acute development of signs.
FBC with differential: elevated WBC.ESR: elevated.CRP: elevated.Fluid cell count: elevated.Fluid Gram stain/culture: may be positive for causative bacteria.
Rheumatoid arthritis
Systemic signs and symptoms; other joint involvement; history of bilateral, symmetric pain and swelling of the small joints of the hands and feet that has lasted for >6 weeks; morning stiffness; rheumatoid nodules over the extensor surfaces of tendons, or vasculitic skin involvement.
ESR: elevated.CRP: elevated.Fluid cell count: elevated.Rheumatoid factor: positive in 70%.
Gout
Swelling, effusion, warmth, erythema and/or tenderness of the involved joint(s).
Plain x-ray: degenerative changes.Uric acid: elevated.

Tension-type headache

Chronic migraine
Routine movement aggravates migraine. History of episodic migraine. Increase in frequency to >15 headache days per month. tension-type headache is often misdiagnosed as migraine in up to 32% of patients. [8] The worsening of pain with activity, presence of nausea, and severe intensity is common with migraine and inconsistent with tension-type headache.
Clinical diagnosis.
Medicine overuse headache
History of previous primary headache. Use of analgesics and ergotamine at a high frequency and worsening of headache on discontinuation of medicine. Over several months, frequency and duration increases such that attacks become daily or near daily, although not necessarily more severe.Opioids and barbitutrate-containing analgesics most commonly produce this syndrome.
Clinical diagnosis.
Sphenoid sinusitis
Vertex or frontal pain, often described as pressure, but not necessarily with additional sinus symptoms.
CT sinus to evaluate for acute or chronic sinusitis.
Giant cell arteritis
Generally over 50 years of age. New head pain associated with soreness of the scalp; polymyalgia rheumatica and often jaw or tongue claudication.
ESR and/or CRP typically significantly elevated.
Temporomandibular disorder (TMD)
Pain over temporalis associated with noise and clicking over TMJ with jaw movement. Often associated with bruxism and limited jaw movements, or pain or locking of the jaw with opening of mouth.
Clinical diagnosis.
Pituitary tumour
Abnormal neurological examination. Visual field defects and galactorrhoea may occur.
Apparent on brain MRI.
Brain tumour
Abnormal neurological examination including reflex asymmetry, sensory asymmetry, or motor weakness. Papilloedema suggests an intracranial mass lesion.
Apparent on brain MRI.
Chronic subdural haematoma
Abnormal mentation, abnormal neurological examination including reflex asymmetry, sensory asymmetry, or motor weakness.
Apparent on brain MRI.
Pseudotumor cerebri (idiopathic intracranial hypertension)
Besides papilloedema, there may be reduced visual acuity, visual field defect (enlarged blind spot), or diplopia caused by a 6th nerve palsy. CSF pressures are abnormal and are increased to >200 mm water in non-obese and >250 mm water in obese people.
Normal MRI possibly with small ventricles; most important finding is elevated spinal fluid pressure.
Cervical pathology
Rarely, serious cervical pathology such as a herniated disc may contribute to headache.
MRI scan reveals disc herniations and soft-tissue masses.

Testicular cancer

Testicular torsion
Typical history of sudden onset of testicular pain.Physical examination shows a horizontal, rotated, high- riding testis, painful to touch. This is in contrast to a low testis in standing position characteristic of testicular mass.Neonates typically present with a unilateral swollen and discoloured scrotum of sudden onset.
Ultrasound shows a diffuse hypoechogenicity and enlargement when compared with the contralateral side. However, the testis may appear normal in the first 6 hours. In these cases a rotated spermatic cord on examination can be a highly reliable and direct sign. Doppler ultrasound will detect blood flow occlusion in most cases after the first 6 hours. Heterogenicity after 24 hours indicates infarction and haemorrhage. Markers are negative.
Epididymo-orchitis
Signs of inflammation (erythema, warmth, and pain) may occur and are not usually seen with malignancy.Clinical history is usually shorter (<2 weeks).
Colour Doppler imaging characteristically shows increased blood flow to the testicle and epididymis. Occasionally an abscess can be detected in immunocompromised patients. If there is doubt, tumour markers may be checked, which should be negative.Diagnosis by urethral swab and culture can detect associated STDs. [36]Chronic orchitis may present as a shrunken testis with increased echogenicity on ultrasound. Thickening of the capsule and fluid collections can be seen surrounding the testis.
Scrotal hernia
Bowel sounds may be heard on examination. If the mass can be reduced on palpation this indicates a hernia.
A characteristic scrotal ultrasound finding is herniated bowel in the scrotum. The bowel herniates through a patent processus vaginalis and is separate from the testis. Loops of bowel with peristaltic movements and omentum can be seen.
Hydrocele
On physical examination the mass transilluminates with light. The fluid collection usually engulfs the whole testis so the testis cannot be palpated. However, a testicular mass can coexist with hydrocele and should be ruled out by scrotal ultrasound.
High-resolution ultrasound will differentiate from intratesticular solid mass. The mass is translucent and surrounds the whole testis.
Epididymal cyst
Scrotal mass that can be transilluminated. The position of the cyst helps the diagnosis. The cyst can be palpated separately from the testis, lying posterior and superior to it. [37]
Scrotal ultrasound may assist in making the diagnosis.
Haematomas
There may be a recent history of blunt trauma. However, up to 10% of testicular cancer also presents after a history of trauma. [30]
There are no specific tests. Diagnosis is made based on history of trauma and clinical examination.Ultrasound may show a break in the tunica albuginea, testicular contour irregularity, and poorly defined borders of the testicle. Serum tumour markers are negative.
Spermatocele
On examination this should be separate from the testis and near the high pole. Easily distinguished using a scrotal ultrasound.
Ultrasound is reliable in visualising a small fluid-filled cyst.
Intratesticular benign cysts
Most are not palpable except when they are at the periphery of the testis. These include intratesticular simple cysts, tubular ectasia, epidermoid cyst, tunica albuginea cyst, and intratesticular varicocele.
Ultrasound will detect a fluid-filled cavity within the testis in almost 100% of the cases. [38]
Syphilitic gumma
Inflammatory, fibrous nodules that may cause local destruction. Can occur anywhere but most often affect the bone and skin.Gumma are a late manifestation of syphilis. May have a history of secondary syphilis. Signs of early syphilis include general lymphadenopathy, and genital and mucosal ulceration. Signs of late syphilis include pupillary changes (Argyll-Robertson pupil) and aortic regurgitation. [39]
Positive treponema pallidum serology.

Testicular torsion

Testicular appendix torsion
Pain located superiorly on testicle; onset is more gradual than in testicular torsion.Not associated with symptoms such as nausea and vomiting.Blue spot can be observed through the scrotal skin: the 'blue dot sign'.On physical examination, there may be a normal cremasteric reflex.
Colour Doppler ultrasound will demonstrate increased blood flow.Urinalysis usually normal.
Epididymitis or epididymo-orchitis
Pain located inferiorly and posterior to testicle.Pain and swelling typically develops over the course of a few days, unlike testicular torsion, which is usually of sudden onset.The epididymis can be felt as a tubular structure that lies posterior to the testis and runs in a sagittal plane.Diffuse enlargement of the testis will be present in epididymo-orchitis.Frequent and painful micturation are common features of lower urinary tract infection that can be associated with epididymitis.
Colour Doppler ultrasound confirms the diagnosis: epididymis is enlarged and hyperaemic.Diagnosis by urethral swab and culture can detect associated STDs (e.g., positive culture of Neisseria gonorrhoeae or Chlamydia trachomatis).May have an abnormal urinalysis.
Hydrocele
On physical examination the mass will trans-illuminate with light.The scrotal mass is likely to be soft if the communication is large or tense if it is small. It may be restricted to the scrotum or it may extend into the inguinal canal.There may be enlargement of scrotal mass following activity and variation in scrotal mass during the day.
Scrotal ultrasound confirms presence or absence of normal/abnormal testis.Trans-illumination when a focused beam of light is shone on the scrotum.
Varicocele
Painless scrotal mass. Palpation of enlarged veins during Valsalva manoeuvre is diagnostic on physical examination.
Physical examination is diagnostic, but colour Doppler ultrasonography can be used for confirmation.Scrotal ultrasound with colour flow Doppler imaging will show presence of varicocele or identification of subclinical varicocele.
Testicular cancer
There may be no pain.Mass has a gradual onset and may be an incidental finding on examination.Not usually associated with sudden-onset testicular pain unless possibly associated with epididymo-orchitis or intra-tumoural haemorrhage. [9]
Ultrasound colour Doppler will show testicular mass.CT scan of the abdomen and pelvis will show enlarged lymph nodes.Testicular tumour markers, such as beta-hCG and alpha-fetoprotein, may also be used to indicate tumour activity.Trans-inguinal biopsy for pathological confirmation. Extra-testicular tumours are usually benign; intra-testicular tumours are usually malignant. [16] [9]
Scrotal haematoma
On physical examination, there may be a normal lie of the affected scrotum and a normal cremasteric reflex on the affected side.
Ultrasound may show an intra-testicular or extra-testicular mass. Acute haemorrhage would appear hyper-echoic. [9] As haemorrhage ages, the ultrasound appearance would appear hypo-echoic or develop into a complex cyst. [9] Ultrasound should not show vascular flow because haematomas lack vascularity.
Isolated orchitis
Signs of inflammation (erythema, fever, and pain) may be present.Mostly caused by mumps or HIV.If sexually active, suspect STD.
Ultrasound will show an enlarged testis with diffuse, focal, or multi-focal hypo-echoic lesions. [9]Increased blood flow on colour Doppler. [9]Urinalysis is not helpful in diagnosing isolated orchitis because the aetiology is usually of viral origin.
Scrotal abscess
May be fever and may detect fluctuant mass.
Ultrasound may show an irregular scrotal wall and low-level internal echoes. [9]
Fournier's gangrene
Clinically the patient will appear ill, and will possibly be septic.There may be fever and may detect necrotic tissue and crepitus.
Ultrasound will show thickening of scrotal skin with a normal testicle. [9] The pathognomonic ultrasound finding is multiple hyper-echoic foci within the scrotal skin indicating gas within the scrotal wall. [9]CT pelvis will show soft-tissue gas with possible fascial thickening and fat stranding. The aetiology of Fournier's gangrene may be identified: that is, peri-anal abscess or an incarcerated inguinal hernia.
Inguinal hernia
May be a history of heavy lifting or previous surgery.May detect a mass in the inguinal canal that may be non-reducible. [18]Inguinoscrotal swelling with inability to palpate the spermatic cord superiorly.On physical examination, there may be a normal lie and a normal cremasteric reflex.
Ultrasound will show abnormal ballooning of the anteroposterior diameter of the inguinal canal and, occasionally, a pad of fat or segment of the bowel is seen.CT of groin will show solid mass in the groin that follows the course of the spermatic cord.
Renal colic
Flank pain.On physical examination, there may be a normal lie and a normal cremasteric reflex.
Ultrasound may reveal hydronephrosis or hydro-ureter on the affected side.Spiral CT of the abdomen/pelvis may show the location and size of the renal stone.Urinalysis will show microscopic haematuria.
Henoch-Schonlein purpura
Physical examination may reveal a palpable skin rash, colicky abdominal pain, or arthralgias.May also be scrotal tenderness and/or ecchymosis mimicking testicular torsion. [9] The incidence of scrotal manifestations (e.g., painful swelling and ecchymosis) ranges from 2% to 38% of cases of Henoch-Schonlein purpura, and about 3% of all cases of acute scrotum are caused by scrotal involvement of Henoch-Schonlein purpura. [9]History of prior upper respiratory tract infection.
Urinalysis may show RBCs, proteinuria, or casts.Ultrasound of abdomen may show intussusception or perforation, or testicular swelling.Ultrasound of testicles may show testicular swelling.
Acute appendicitis
Right lower quadrant abdominal pain, and possibly fever, nausea, and vomiting.
Ultrasound or CT of the abdomen would reveal an inflamed appendix.FBC may be normal.
Spermatocele
Soft, freely mobile trans-illuminating mass separate from and superior to the testicle. [16]
Ultrasound is rarely needed to confirm the diagnosis.Ultrasound would reveal a well-defined hyper-echoic lesion. [16]
Idiopathic testicular infarction
Sudden-onset testicular pain.May develop oedema and erythema.
Rare entity with no definitive diagnostic test. Emergent urological consult and early surgical exploration is advisable. [19]

Tetanus

Drug-induced dystonias, for example, phenothiazines
Features may include torticollis, retrocollis, trismus, glossopharyngeal dystonia, opisthotonu, and often deviation of the eyes. Tetanus is not associated with ocular deviation.A compatible drug history would support a diagnosis of drug-induced dystonia.
Anticholinergic agents such as procyclidine usually ameliorate drug-induced dystonias but have no effect on tetanus.
Strychnine poisoning
Strychnine is a white, odourless, poisonous powder that can be taken by mouth, inhaled (e.g., mixed with cocaine/heroin) or injected intravenously in solution. It is a competitive antagonist of the inhibitory neurotransmitter glycine at receptors in the spinal cord, brainstem, and higher centres.Symptoms of poisoning usually appear within 15 to 60 minutes of ingestion and include heightened awareness, agitation, restlessness, painful muscular spasms and rigidity, trismus, opisthotonus, and hyper-sensitivity to stimuli. [31] Respiratory muscle spasm can cause respiratory arrest.Ingestion of large amounts can lead to painful generalised convulsions, during which the patient retains consciousness.Patient may give a history of snorting street drugs or deliberate/accidental ingestion of strychnine, which may be present in pesticide preparations, particularly rat poison.
Blood, urine, and tissue assays for strychnine should be requested in suspected poisoning or when apparent tetanus presents in a fully immunised patient or in the absence of an antecedent tetanus-prone injury.
Neuroleptic malignant syndrome
An idiosyncratic reaction to a neuroleptic medicine, featuring rapid onset of hyperthermia, muscular rigidity, extrapyramidal signs, autonomic dysfunction, mutism, confusion, and even coma. Tremor and urinary incontinence may be present.The condition is attributed to dopamine receptor blockade. The patient's drug history should indicate a possible cause. All classes of neuroleptic agents (dopamine D2 receptor antagonists) have been implicated, as well as non-neuroleptic agents, which block central dopamine pathways such as metoclopramide.It is more likely to develop after initiation of neuroleptic therapy or an increase in dose, but can occur at any time during treatment, even years after starting therapy. Withdrawal of anti-Parkinson medicine can also precipitate the syndrome.Altered mental status is less common in tetanus.
Clinical diagnosis.
Stiff man syndrome
Severe progressive muscle rigidity of the trunk and limbs with superimposed spasms, which may be triggered by voluntary movements, external stimuli, or emotional stress.Trismus and facial spasms are absent.The patient may suffer unprotected falls like a tin soldier.Symptom onset is typically between the ages of 30 and 50 years. Most cases begin insidiously and progress over years, although some can develop over weeks.Patients often have other autoimmune conditions.
Glutamic acid decarboxylase autoantibodies in 60% of patients. EMG reveals a characteristic abnormality. There is a rapid response to diazepam.
Hypocalcaemia
Peri-oral and peripheral numbness/tingling and muscle cramps, which may progress to carpopedal spasm.There may be a history of irritability, confusion, reduced intellectual capacity, or depression. Seizures can occur as well as movement disorders, for example, choreoathetosis, dystonic spasms, Parkinsonism, and hemiballismus.Wheezing may arise due to bronchospasm. Cardiac abnormalities include arrhythmias and congestive heart failure.Clinical signs of chronic hypocalcaemia may be present, for example, brittle nails, coarse hair/alopecia, dry skin.The patient's history, drug history and physical examination may suggest an underlying cause for hypocalcaemia. Bisphosphates, anticonvulsants, foscarnet, and cisplatin can lead to hypocalcaemia.It may be possible to elicit Chvostek and Trousseau signs, which are suggestive of hypocalcaemia.
Hypocalcaemia is confirmed by laboratory measurement of ionised calcium. ECG may show prolonged QT interval. Further investigations may establish the underlying cause: phosphate, alkaline phosphatase, magnesium, PTH, 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D, renal and liver function, amylase, etc.
Dental/parapharyngeal/parotid/tonsillar infection or diphtheria
These infections can cause trismus without spasms or generalisation.Localised swelling, tenderness, or exudate may be apparent.
Radiological imaging may confirm deep abscesses.
Meningitis
Meningitis and meningoencephalitis can produce trismus, rigidity, seizures, and opisthotonus, but risus sardonicus is absent. [19]
The CSF findings differentiate between these conditions and tetanus. The protein may be slightly elevated in tetanus, but the cell count is normal. [19]
Generalised seizures in children
The differentiation between seizures and tetanus may be particularly difficult in neonates. However, in epilepsy consciousness is impaired, and the muscles are often hypotonic and flaccid in the postictal state. [19]
Abnormal EEG in epilepsy.

Tetralogy of Fallot

Other cyanotic congenital cardiac abnormalities
Includes single ventricle lesions such as hypoplastic left heart syndrome or tricuspid atresia. Other possibilities include D-transposition, pulmonary atresia, anomalous pulmonary venous connection, truncus arteriosus, or Ebstein's anomaly.These may all be difficult to differentiate clinically from a cyanotic newborn with TOF. Most are not specifically associated with other syndromes, although this can vary.
No change in PaO2 with hyperoxia test.Echocardiogram can define anatomy to classify cyanotic heart disease.In some cases, a cardiac catheterisation may be needed to further define anatomy and physiology.
Pulmonary stenosis
Usually presents in an asymptomatic patient with a systolic ejection murmur on examination. Difficult to differentiate clinically from TOF. [20]
Echocardiogram will show presence or absence of typical anatomy of TOF with pulmonary obstruction to differentiate from pulmonary stenosis alone.
Ventricular septal defect (VSD)
At birth, an infant with simple VSD is fully saturated with regurgitant murmur on examination.Intensity of murmur depends on size of VSD and flow across the VSD. A small VSD has a louder murmur because the gradient between the right and left ventricles is higher. A large VSD has a soft murmur because pressures are equalised between the right and left ventricles.As pulmonary vascular resistance drops, more blood shunts from left to right across the VSD and may result in pulmonary over-circulation and heart failure. This is uncommon with TOF, as the pulmonary obstruction prevents over-circulation.
Echocardiogram will show presence or absence of right-sided obstructive lesion to determine whether this is VSD alone or TOF.
Double outlet right ventricle with normally related great vessels and pulmonary stenosis
Cannot be differentiated from TOF on physical examination alone.
Echocardiogram will show presence or absence of subaortic conus and degree of aorta over-ride of the VSD to differentiate TOF from double outlet right ventricle.
Primary pulmonary disease
On examination, infant may be tachypnoeic and desaturated, potentially requiring mechanical ventilation.Cardiovascular examination is usually normal.
Hyper-oxygenation test should show increase in PaO2 with administration of 100% FiO2.CXR will show normal cardiac silhouette with increased lung markings.Echocardiogram will show normal intracardiac anatomy.

Thoracic outlet syndrome

Carpal tunnel syndrome
Pain and numbness primarily in the wrists; night-time worsening of symptoms.
Electrodiagnostic testing showing focal slowing of conduction velocity in the median sensory nerves across the carpal tunnel.
Cubital tunnel syndrome
Pain and numbness primarily in the elbow through the ring and little fingers.
Electrodiagnostic testing showing motor conduction velocity across the elbow is <50 m/second.
Herniated cervical intervertebral disc
Pain in upper extremities, specifically the back, radiating down through the buttocks and legs, possibly with muscle spasms. [39]
MRI cervical spine showing herniation of cervical intervertebral disc.
Ruptured cervical disc
Pain down medial aspect of the arm.
MRI cervical spine showing herniation of cervical intervertebral disc contents.
Cervical spondylosis
Stiffness in upper neck, loss of bladder or bowel control, urinary or bowel retention.
Cervical spine x-ray showing cervical spondylitic degeneration.
Vascular occlusion, embolism, or insufficiency
Severe chest pain.
Angiogram showing narrowing or occlusion of affected vessel.
Coronary artery disease
Chest pain.
Coronary angiogram showing narrowing or occlusion of affected vessel.
Myocardial infarction
Severe chest pain, dyspnoea, pallor, diaphoresis, and cardiogenic shock.
ECG in ST-elevation MI: ST-segment elevation >1 mm in 2 or more anatomically contiguous leads or new left bundle branch block; ECG in non-ST-elevation MI: non-specific changes; ST-segment depression or T-wave inversion.
Angina pectoris
Chest pressure or squeezing promoted by exercise or emotional stress.
ECG showing non-specific changes; ST-segment depression or T-wave inversion.
Primary Raynaud's phenomenon
Blue or purple colour in hands or fingers.
Diagnosis is clinical.
Superior pulmonary sulcus carcinoma
Severe chest pain.
CT chest demonstrating superior pulmonary sulcus carcinoma.
Superior sulcus tumour
Shoulder and elbow pain. [40]
CT chest demonstrating tumour. [41]

Thoracolumbar spine trauma

Musculoskeletal lower back pain
Patient may have history of obesity, stress, and psychiatric comorbidities; previous lower back pain; or prior treatment for lower back pain.Absence of red flag symptoms (recent significant trauma, or milder trauma in age >50 years; unexplained weight loss; immunosuppression; history of cancer; IV drug use; prolonged use of corticosteroids; osteoporosis; age >70 years; focal neurological deficit with progressive or disabling symptoms; or duration of lower back pain >6 weeks). [44]Sensory, motor, and deep tendon reflexes within normal limits.
Plain x-rays: normal.MRI/CT spine: absence of disc herniation and spinal stenosis.
Acute cervical spine trauma
History of neck injury or pain, or radiculopathy. Sudden onset of radicular symptoms after trauma. Head strike with or without loss of consciousness.
Cervical x-ray: ligamentous instability may be seen in the form of excessive (>2 mm) anterior or posterior vertebral body translation relative to the vertebra below; avulsion or teardrop fracture may be seen at the anterior vertebral body; fractures of atlas (C1) and axis (C2) are known even in relatively lower energy events, including hangman fracture of the axis; in more severe injury mechanisms (particularly with airbag deployment), unilateral and even bilateral facet luxation may be present with or without fracture.
Degenerative cervical spine disease
Cervical spondylosis is associated with increasing age (>40 years), and there may be a family history or history of trauma, myofascial strain, or cervical surgery.Spontaneous onset of neck pain. Cervical muscle pain and spasm. Headache or occipital pain.
Cervical x-ray: presence of degenerative joint disease or degenerative disc disease, fracture, or instability.Cervical MRI: bone destruction, spinal cord or nerve compression, intradural or epidural process.
Osteoporosis
Risk factors include: older age (women >50; men >65); predominantly female gender; white ancestry; FHx of hip fracture; prior fracture.History of low-impact injury.Examination findings: loss of height, kyphosis.
Dual-energy x-ray absorptiometry (DXA): score of ≤-2.5 indicates osteoporosis; T-score ≤-2.5 with fragility fracture(s) indicates severe (or established) osteoporosis.X-ray: can reveal osteopenia.Quantitative CT: shows reduced trabecular bone density.
Spinal osteosarcoma
Rare. Worsening pain over weeks or months. Mass or swelling found on examination.
X-ray: radiolucent lesion with areas of mottled radiodensity and ill-defined margins.
Metastatic bone disease
History of cancer.History of low-impact injury.
CT/MRI/MRI FLAIR (fluid-attenuated inversion recovery): detection of tumour.

Thrombotic thrombocytopenic purpura

Haemolytic uraemic syndrome (HUS)
More commonly seen in children.Patients demonstrate more renal failure and fewer neurological symptoms.Some experts believe that it is impossible to distinguish between TTP and HUS and that they are a continuum of a pathology, whereas others believe that they are distinct entities.Caution should be used in making this diagnosis because it would be harmful to withhold potentially life-saving plasma-exchange treatment if the true diagnosis is TTP.
Associated with Escherichia coli O157:H7 infection, which is detected in the stool.
Hypertension, malignant
Patients can present with microangiopathy, anaemia, thrombocytopenia, renal impairment, and neurological dysfunction. However, it is extremely unlikely that a patient with TTP will present with severe HTN.Microangiopathic haemolysis in patients with malignant HTN clears and thrombocytopenia resolves with BP management.Patient will have severe HTN, for example, systolic BP >200 mmHg, diastolic BP >130 mmHg.
Clinical diagnosis.
DIC
DIC patients typically appear more acutely unwell than patients with TTP. They can also have delayed bleeding after trauma, such as needle pricks.Sometimes DIC associated with occult or frank malignancies can be hard to distinguish from TTP. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with TTP have atypical clinical features or do not respond to plasma exchange. [30]
Prolonged prothrombin time and activated partial thromboplastin time with raised D dimer suggests DIC.
Sepsis
Sepsis patients have hypotension, fever, and other signs of sepsis. Treatment of the underlying infection should correct the thrombocytopenia.
Patients often have more pronounced fever and raised white count with left shift. Peripheral smear might show vacuoles in the cytoplasm of neutrophils, which is highly specific for bacteraemia. Blood cultures might be positive.
Idiopathic thrombocytopenic purpura
These patients do not have renal insufficiency, neurological symptoms, microangiopathy, or fever, which are seen in patients with TTP.
Peripheral smear is bland, other than the presence of thrombocytopenia. They should not have schistocytes.
Pre-eclampsia
New BP elevation and proteinuria after 20 weeks of gestation in pregnant woman.Although pregnancy is a risk factor for TTP and proteinuria can be present, patients with TTP do not generally have raised BP.
Clinical diagnosis.
Haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome
It can be difficult to distinguish between TTP and HELLP syndrome in some pregnant women. HELLP is suggested by preceding proteinuria and HTN followed by pre-eclampsia. HELLP develops in the third trimester, whereas TTP can occur at any point during pregnancy.
Blood work shows haemolysis with a microangiopathic blood smear, raised liver enzymes, and a low platelet count. Might have evidence of DIC on coagulation studies.
Connective tissue disorder-associated vasculitis
Clinical features of connective tissue disease such as SLE or antiphospholipid syndrome. [31]
Positive ANA in SLE.Positive anticardiolipin and anti-beta-2-glycoprotein I antibodies in antiphospholipid syndrome.
Haemorrhagic fevers
History of travel to an endemic area.Lead to haemorrhagic manifestations including petechiae, ecchymoses, or overt bleeding from gums, nose, mucosae, or phlebotomy sites. May mimic TTP.
Peripheral blood smear usually negative but may reveal schistocytes.Serological testing confirms diagnosis.

Thymic tumour

Lymphoma
History of persistently enlarged lymph nodes, constitutional or B symptoms (fevers, night sweats, and/or weight loss). Physical examination reveals lymphadenopathy in one or more regions; hepatosplenomegaly may be present.
Chest CT scan usually shows matted lymphadenopathy. Peripheral lymph node excision biopsy will reveal type of lymphoma.
Seminoma
Occurs in people aged 20 to 40 years, with male predominance.Presenting symptoms depend on tumour location, growth rate, and size; they include chest pressure, hoarseness, chest wall pain, dysphagia, and dyspnoea.
Chest CT scan usually shows homogeneous invasive malignant-appearing anterior mediastinal mass.Serum alpha-fetoprotein normal; may have low-level elevation of serum beta-hCG.
Non-seminomatous germ cell tumour
Patient is typically a young male with significant symptoms of systemic and local invasion, such as fatigue, weight loss, fever, dyspnoea, and chest pain.
Serum alpha-fetoprotein and beta-hCG usually elevated.Chest CT scan usually shows a large, inhomogeneous invasive mass with areas of haemorrhage and necrosis; pleural effusion often present; may show lung metastases.
Substernal goitre
Older patient usually without symptoms. Rarely, patients have upper-chest discomfort, dyspnoea, or hoarseness. Symptoms of hyperthyroidism (heat intolerance, weight loss, insomnia) may be present.A visible goitre is present in 80% to 90% of patients; substernal extension is suggested if the lower pole of the thyroid gland cannot be identified. Airway compression may present with stridor and prolonged inspiration/expiration. Signs of thyrotoxicosis, including weight loss, hypertension, and tachycardia, may be evident on physical examination. Tracheal deviation can occur if the goitre is asymmetrical. Pemberton's signs (neck vein distension and facial flushing when arms are held vertically above head [Pemberton's manoeuvre]) may be present.
Chest CT shows anterior mediastinal mass contiguous with the thyroid; mass often has low-density areas and calcifications.
Thymic hyperplasia
Always asymptomatic. Can be seen with myasthenia gravis, Graves' disease, burns, following viral illnesses, and as a rebound phenomenon (e.g., following chemotherapy, especially for Hodgkin's disease).
Chest CT usually shows residual shape of bilobed thymus without a dominant rounded mass. View imageChemical-shift MRI may be helpful in differentiating hyperplasia from tumour in problematical cases.

Thyroid cancer

Benign thyroid nodule
These may lack hard consistency, fixation, or associated adenopathy. Vocal cord paralysis is generally absent. However, these findings are not diagnostic.
Fine-needle biopsy generally shows benign cytology with abundance of colloid.For follicular cell adenomas, permanent surgical pathology shows lack of vascular and capsular invasion.

Tic disorders

Tourette's syndrome
Tic disorders are a clinical spectrum that ranges from mild transient tics to Tourette syndrome. [2]
Clinical diagnosis, made by fulfilling criteria for Tourette syndrome: [16]Both multiple motor tics and ≥1 vocal tics must be present at the same time, although not necessarily concurrently.The tics must occur many times a day (usually in bouts), nearly every day or intermittently over >1 year, during which time there must not have been a tic-free period of >3 consecutive months.The age at onset must be <18 years.The disturbance must not be due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease or postviral encephalitis).
Seizures
If the patient experiences alteration of consciousness, or if the movements cannot be temporarily suppressed or controlled, the patient may be experiencing focal motor seizures or myoclonic seizures and not motor tics. [1] [3]
If the history does not differentiate tics from seizures, an EEG is indicated.
Paediatric auto-immune neuropsychiatric disorders associated with streptococcal infection (PANDAS)
The diagnosis of PANDAS and its association with tic disorders remains controversial. [17]PANDAS is characterised by at least 2 episodes of abrupt onset of tics and obsessive-compulsive behaviours, following a group A streptococcal infection in children between 3 and 12 years of age.An episodic (relapsing, remitting) course, distinct from the smoother waxing, waning course typical in tic disorder.
Positive throat culture for group A streptococci associated in time with an exacerbation of tic symptoms.ASO titers and antiDNase B will be elevated if symptoms have been present for >1 week. [11] [14]ASO titres can be repeated during remission periods to document temporal association. However, the presence of elevated ASO titres only identifies prior infections and does not demonstrate causality.The American Heart Association and the American Academy of Pediatrics have jointly released a scientific statement that states that they do not recommend laboratory testing for PANDAS. [20]
Dystonia
Repetitive twisting and sustained involuntary movements that may be slow or rapid.Movements are not preceded by any premonitory sensation and they are unable to be temporarily suppressed. [1] [3]
Diagnosis is usually based on history and physical examination.
Stereotypies
Movements are repetitive, stereotyped, and purposeless, elicited by excitement, anxiety, and occasionally boredom.Typical movements include hand flapping, rocking, or chewing.Stereotypies are common in children with autism or mental retardation, although may be present in children with no other conditions. [1] [3]Typically do not start in the face or neck.
Diagnosis is usually based on history and physical examination.
Myoclonus
Movements are generally more rapid than the brief movement of most tics.Myoclonus is not suppressible.The condition may be physiological (such as sleep myoclonus) or pathological (such as seen with myoclonic epilepsies). [1] [3]
Diagnosis is usually based on history and physical examination.An EEG may be helpful to distinguish myoclonic seizures from tics.
Tremor
Involuntary, oscillatory movement of a body part that is rhythmic compared with the movements due to tic disorder. [1] [3]
Diagnosis is usually based on history and physical examination.
Chorea
Continuous, involuntary, rapid, random movements that tend not to be repeated stereotyped movements.Acute rheumatic fever may be present. Chorea is most commonly due to Sydenham's chorea (one of the clinical manifestations of acute rheumatic fever). [1] [3]
Diagnosis is usually based on history and physical examination.
Ballismus
Movements are large amplitude and typically unilateral. [1] [3]
Diagnosis is usually based on history and physical examination.
Athetosis
Movements are writhing and slow. [1] [3]
Diagnosis is usually based on history and physical examination.

Tinnitus

Meniere's disease
Presents with a quadrad of symptoms: tinnitus, episodic vertigo lasting 15 minutes to 24 hours, unilateral aural fullness, and hearing loss.In most cases only one ear is involved, but the condition is bilateral in 10% to 30% of cases. [28]
Clinical diagnosis.Audiometry usually reveals unilateral sensorineural hearing loss.
Acoustic neuroma (schwannoma)
Benign tumour that commonly arises from the vestibular nerve.As the tumour grows it compresses the cochlear and vestibular nerves, usually causing unilateral hearing loss, tinnitus, and dizziness. Can also interfere with the trigeminal nerve, causing facial numbness.If the tumour becomes large, it will eventually compress the fourth ventricle and cause hydrocephalus and life-threatening brainstem compression.
MRI is necessary to rule out acoustic neuroma in patients with subjective unilateral tinnitus, asymmetrical audiogram, and normal ear examination.
Glomus tumour
Glomus tympanicum tumours arise from the cochlear promontory and are usually visible otoscopically as a red, pulsatile mass behind an intact tympanic membrane.Glomus jugulare tumours arise from paraganglia in the adventitia of the jugular bulb. When a glomus jugulare tumour is confined to the jugular fossa, otoscopic examination is normal.Both types of glomus tumour can cause pulsatile tinnitus in 60% of patients. [3]
Small glomus tympanicum tumours are best seen on high-resolution computer tomography (HRCT) scans.The earliest abnormality detectable on cross-sectional images of a glomus jugulare tumour is erosion of the lateral and anterior walls of the osseous jugular fossa on HRCT scan.
Dehiscent jugular bulb
Most common cause of diagnosable pulsatile tinnitus. [3]Jugular bulb is the dilation of upper jugular vein between the sigmoid sinus and the jugular vein at the junction. A high-riding jugular bulb is above the level of the floor of the external auditory canal or tympanic annulus.A dehiscent high jugular bulb is visible at otoscopy as a smooth, bluish mass. [29]
Visible on MR angiography.Thin-section bone algorithm CT scans demonstrate the anatomy of temporal bone better and help in the diagnosis. [29]
Otosclerosis
The hard, mineralised bones of the inner ear turn into a more vascular and immature bone, resulting in excessive bone growth and fixation of the stapes at the oval window.Eventually leads to conductive hearing loss.Approximately 90% of people with otosclerosis are unaware of their hearing loss and do not seek treatment when the loss is mild. Tinnitus is present in 75% of patients with otosclerosis and is characterised by a broad-band hissing sound, humming sound, or discrete tones.
Conductive hearing loss on audiometry.
Otitis media
Associated with fever, earache, nausea, vomiting, or tinnitus.Diagnosed by otoscopy and visualisation of red, bulging tympanic membrane. Decreased movement of tympanic membrane is the main diagnostic factor of otitis media.
Clinical diagnosis.
Myoclonus
Tensor and levator veli palatine, salpingopharyngeus, and superior constrictor muscle myoclonus are all causes of objective tinnitus.Myoclonus of these muscles leads to rhythmic involuntary jerking movements of soft palate and causes tinnitus that has a clicking nature. [3] [7]
Clinical diagnosis.
Multiple sclerosis
Demyelinating disease of the central nervous system. Tinnitus, with or without hearing loss, has been reported during exacerbation of the disease by a minority of patients.
MRI of the brain with gadolinium confirms white matter lesions.
Patulous eustachian tube
Usually occurs after adenoidectomy or weight loss.Causes clicking sounds with swallowing, aural fullness, autophony.Head-hanging relieves the symptoms due to dilation of veins. [3]
Diagnosed by otomicroscopy that shows movement of tympanic membrane with respiration.
Cerebrovascular disease
Tinnitus occurs if there is turbulence of the blood flow in a narrow or abnormal artery.Aneurysms, atherosclerosis, and aberrance of carotid artery can result in pulsatile, objective tinnitus.Atherosclerosis of carotid artery can be suspected in patients with risk factors such as hyperlipidaemia, hypertension, diabetes, and smoking.Audible carotid bruit on physical examination.Aberrant carotid artery may be visualised in the mesotympanum as a red or white mass that does not blanch with pneumo-otoscopy.
Diagnosed on duplex ultrasonography.CT scan can also show the aberrant carotid artery.
Arteriovenous malformation (AVM)
Dural AVMs occasionally present with pulsatile tinnitus.Audible bruits can be heard by auscultation of the retroauricular region.
Diagnosed on MRI and MR angiography (MRA).Carotid angiography should be considered if no disease was found on MRA and clinical suspicion is high. [3]
Dural arteriovenous fistula (AVF)
Present with pulsatile tinnitus in 65% of patients in association with visual changes, headache, or mental status change. [30]
Diagnosed on MRA or carotid angiography. [3]
Salicylate overdose
Ingestion of about 150 mg/kg of salicylate produces mild toxicity, and >500 mg/kg of this drug is lethal.Presents with acute onset of tachypnoea, tachycardia, hypotension, seizure, encephalopathy that may progress to coma.Auditory symptoms of tinnitus and deafness.Tinnitus occurs when serum salicylate concentration exceeds 30 mg/dL.
Elevated serum levels of salicylate.

Tonsillitis

Infectious mononucleosis
More common in slightly older age group (adolescents) and, unlike acute tonsillitis, does not resolve after 1 week.It is associated with generalised lymphadenopathy, splenomegaly, and hepatomegaly, and persistent weight loss and fatigue.Rarely, the swelling of the pharyngeal tissues may become so significant as to impair breathing.
Heterophile antibody testing is most commonly used to diagnose infectious mononucleosis. However, it has only moderate sensitivity, particularly in the first week of symptoms; sensitivity is even lower in children than it is in adults. [13]
Epiglottitis
A child with epiglottitis will have a muffled voice and will be drooling; there may be stridor and difficulty in breathing.
On suspicion of epiglottitis, it is important not to spend time performing blood tests or even attempting to examine the child's throat: prompt consultation with a paediatric anaesthetist to secure the airway is crucial.
Peri-tonsillar abscess (quinsy)
Causes more severe symptoms, including trismus, a muffled voice, a displaced uvula, and an enlarged, displaced tonsil, with swelling of the peri-tonsillar region.
The diagnosis is based on examination of the oropharynx and is confirmed on needle aspiration of pus from the peri-tonsillar swelling.
Retropharyngeal abscess
Symptoms may be similar to those of a severe sore throat.However, the symptoms do not resolve after a few days, and there may be trismus or visible neck swelling.
Exclusion is made on the basis of lateral neck x-ray, or neck CT or ultrasound.
Gonococcal pharyngitis
Adolescent and adult patients with a history of oral-genital sex.
Throat culture (in Thayer-Martin medium) of Neisseria gonorrhoeae.
Diphtheria
Examination of the oropharynx reveals the typical grey-green membrane.Serosanguineous nasal discharge will be noted.Patient will not have been immunised against diphtheria.
Microbiology showing Corynobacterium diphtheriae.
HIV infection
Patients with primary HIV infection are more likely to have generalised lymphadenopathy, weight loss, and malaise, and to have risk factors for HIV infection.
Diagnosis is made by a positive HIV test.

Torsion of the lower limb in children

Metatarsus primus varus
Isolated adducted first metatarsal.Normal alignment of lateral border of foot.Vertical skin crease at the tarsometatarsal joint on the medial side of the foot.
Foot x-rays. Angulation of the first metatarsal bone towards the midline of the body.
Positional calcaneovalgus
Identified at birth.Ankle dorsiflexed with mild subtalar joint eversion.Ankle dorsiflexion is flexible.
Clinical diagnosis. Routine imaging studies not necessary.
Hip dysplasia
Hip abduction and symmetry should be assessed to rule out hip dysplasia.
Anteroposterior pelvic x-ray may demonstrate dysplasia of the hip.
Congenital femoral deficiency
A spectrum of congenital isolated limb deficiency with a short femur in an otherwise normal child.The affected thigh is shorter than the contralateral thigh, and the leg may be shorter.
Anteroposterior pelvic x-ray and anteroposterior x-ray of the lower extremities.Femoral deficiency ranges from mild shortening to total absence of the proximal femur, and apparent discontinuity between the femoral neck and shaft. Typified by valgus and external rotation deformity of the knee, hip abduction and flexion contracture associated with fibular hemimelia, and absence of the cruciate ligaments of the knee.

Tourette's syndrome

Transient tic disorder
Identical to TS except duration lasts less than 1 year.
Diagnosis is usually based on history and physical examination.
Chronic motor or phonic tic disorder
Patients have either only motor or only phonic tics for more than 1 year.
Diagnosis is usually based on history and physical examination.
Stereotypies
Can be seen in normal children but often in children with pervasive developmental disorders. Common ones include head banging, body rocking, repetitive finger movements, and grunting.
Diagnosis is usually based on history and physical examination.
Akathisia
An abnormal state of excessive restlessness accompanied by a feeling of the need to move about with relief gained after moving. Often seen in the context of dopamine receptor-blocking agent exposure, both acutely and chronically.
Diagnosis is usually based on history and physical examination.
Compulsions and obsessions (including OCD)
Although compulsions are also associated with feelings of inner anxiety, they are characterised by ritualistic behaviour (checking, touching, arranging, etc.) and the need to repeat them in the same manner. Obsessions are closely linked and are defined as recurrent, often undesired, intrusive thoughts.
Diagnosis is usually based on history and physical examination.
Paediatric auto-immune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
This is a controversial topic within the paediatric, neurological, and psychiatric communities. By definition, an exacerbation of tics or OCD in the temporal vicinity of a streptococcal infection.
Positive throat culture.Positive anti-streptolysin O antibodies (peak at 3 to 6 weeks) and antiDNAase B antibodies (peak at 6 to 8 weeks). [37]
Myoclonus
Involuntary brief, jerk-like movement. Can be irregular and is not preceded by the urge to perform the movement.
Diagnosis is usually based on history and physical examination.
Wilson's disease
Kaiser-Fleischer rings, parkinsonism, slow high-amplitude proximal tremor.
Increased serum copper levels and low serum ceruloplasmin levels.MRI with symmetrical T2 hyper-intensities in the bilateral basal ganglia and mesencephalon with sparing of the red nuclei.
Huntington's disease
Involuntary choreic movements that are not associated with an urge to move. By definition, these movements should be random and not stereotyped.
Positive genetic testing for Huntington's disease.

Toxic ingestions in children

Non-toxic causes of wide complex tachycardia
Absence of a history of a toxic ingestion should prompt consideration of non-toxic causes.Successful cardioversion with treatment suggests a non-toxic cause; tachycardia due to an ingested toxin usually persists.
A widened QRS in conjunction with a rightward vector of the terminal 40 msec of the frontal plane QRS suggests a toxic ingestion due to sodium channel toxicity. This is most easily identified as a widened (>1 mm) and enlarged (>1 mm) R wave in a VR and S wave in I and L. Non-toxic causes produce other patterns.Administration of sodium bicarbonate to push the arterial pH to between 7.45 and 7.55 narrows the QRS complex in sodium channel blocker toxicity. A lack of response excludes sodium channel blocker toxicity.Drug screen and drug levels are negative.
Non-toxic causes of status epilepticus
A known diagnosis of epilepsy, with poor compliance to medication.Other non-toxic causes are suggested by sudden-onset severe headache (intracranial haemorrhage), unilateral weakness (stroke), or fever (febrile seizure or CNS infection).
Toxic and non-toxic seizures usually respond to benzodiazepines. Seizures also respond to sodium channel anticonvulsants such as phenytoin.Drug screen and drug levels are negative.
Non-toxic causes of anion gap metabolic acidosis
Clinical distinction is difficult.Absence of a history of a toxic ingestion or features specific to particular ingestions (e.g., vision or hearing loss, severe hypertension, recurrent seizures) should prompt consideration of non-toxic causes.History of type 1 diabetes with a recent illness or sub-optimal insulin therapy should prompt consideration of diabetic ketoacidosis.
Drug screen and drug levels are negative.Hyperglycaemia with ketosis should prompt consideration of diabetic ketoacidosis.Elevated serum urea and creatinine should prompt consideration of both toxic and non-toxic causes of renal failure.
Non-toxic causes of altered mental status
Non-toxic causes suggested by history of head trauma (intracranial bleeding), focal neurological signs (stroke), chest pain (MI), fever with symptoms of infection (sepsis or any acute systemic infection), or abdominal pain with tenderness.
No response to therapeutic trial of antidotes.Drug screen and drug levels are negative.
Volume depletion in children
Clinical evidence of excessive GI losses, haemorrhage, diabetic ketoacidosis with polyuria, burns, heat stroke, fever, heavy exercise, anaphylaxis, sepsis, small-bowel obstruction, or ascites.Signs of dehydration.
Tachycardia is common.BP may be slightly high (early stage) or low (late stage).Drug screen and drug levels are negative.
Non-toxic causes of hypertension
Absence of signs of central agitation or features of the antimuscarinic toxidrome suggests a non-toxic cause.Absence of fever.
Drug screen and drug levels are negative.
Non-toxic causes of fever
Absence of features of sympathomimetic or antimuscarinic toxidromes, and absence of hyperreflexia, myoclonus, or rigidity, may suggest a non-toxic cause.Clinical features of an underlying infection, inflammatory disorder, or malignancy.
Drug screen and drug levels are negative.
Non-toxic causes of bradycardia
Absence of features of the cholinergic toxidrome, or of beta-blocker (peripheral shutdown with hypoglycaemia) or calcium-channel blocker toxicity (peripheral vasodilation with hyperglycaemia), may suggest a non-toxic cause.Absence of a history of a toxic ingestion.
Drug screen and drug levels are negative.Bradycardia responds to normal dose atropine.
Inhalation injury
History of exposure to a residential fire, workplace fire or explosion, or a chemical leak.Similar symptoms to other patients at site of exposure.Respiratory symptoms, including cough, dyspnoea, and tachypnoea.Cyanosis, facial burns, hoarseness, dysphonia, or stridor.
Hypoxaemia on pulse oximetry.Increased carboxyhaemoglobin levels in carbon monoxide poisoning.Air trapping, atelectasis, and airspace opacity on CXR.
Snakebites
History of snakebite, with fang marks, local redness, tenderness, pain, and swelling at wound site.Weakness, dizziness, and perioral tingling or numbness are suggestive of envenomation.There may also be bleeding and extensive swelling.
No distinguishing tests.
Insect or spider bites and stings
History of insect or spider bite or sting with pain, itching, or rash at the site of the bite.Clinical features of anaphylaxis.Pain, muscle cramps, diaphoresis, tremors, paraesthesias, nausea/vomiting, and headache suggest a black widow spider bite.
No distinguishing tests.

Toxic megacolon

Colonic pseudo-obstruction
Typically seen in the elderly when hospitalised for a severe illness.Patients may give history of chronic constipation.No systemic manifestations.
Absence of an elevated WBC count and metabolic abnormalities.Contrast enema will confirm the diagnosis and exclude mechanical causes in most cases.
Acute mesenteric ischaemia
Patients may give history of risk factors for acute mesenteric ischaemia, including coronary artery disease, hypertension, diabetes, smoking, and hyper-cholesterolaemia.Diffuse abdominal pain with systemic manifestations, but abdominal distention is often absent.
Abdominal film findings are often normal in the presence of acute mesenteric ischaemia.CT scan will show signs of bowel wall ischaemia including bowel wall thickening, thumb printing, and pneumatosis.
Large bowel obstruction
A history of constipation may be present.Signs of systemic toxicity are absent in the early stages.There may be a palpable abdominal mass on clinical examination suggesting an underlying malignancy or diverticular mass.
Gaseous distention of the large bowel on plain abdominal film; 'kidney bean' shape seen in volvulus.Contrast enema shows obstruction to contrast at site of lesion; 'bird's beak' appearance seen in volvulus.
Hirschsprung's disease
Diagnosed in infancy or early childhood.Abdominal distention that is usually not accompanied by abdominal pain.Increased anal sphincter tone and presence of constipation, which may be relieved with digital rectal examination.
Abdominal films characteristically reveal rectal and distal large bowel dilatation with collapsed proximal large and small bowel.Absence of ganglion cells on rectal biopsy.

Toxic multinodular goitre

Graves' disease
More common than toxic MNG and occurs in generally younger age group.Auto-immune features, such as exophthalmos or pretibial myxoedema, may be present.Goitre is diffuse rather than nodular. However, long-standing Graves' disease may mimic toxic multi-nodular goitre (MNG).Symptoms of hyperthyroidism are generally more marked than for toxic MNG.
Thyroid scan shows diffuse rather than variegated appearance. Uptake is high.Free thyroid hormone levels are usually higher than for toxic MNG.Often there is evidence of thyroid autoimmunity (i.e., positive thyroid peroxidase antibodies), although this is not diagnostic.When positive, TSH receptor antibodies are diagnostic, but these are rarely required.
Toxic adenoma
Patients tend to be younger (<40 to 50 years).Single, generally large palpable nodule.
I-123 or Tc-99 scan shows a single hot area with suppression of extra-nodular tissue.View image
Thyrotoxic phase of painless/lymphocytic thyroiditis
Most often occurs postpartum.
Absent or low uptake on I-123 scan, in contrast to generally normal uptake in toxic MNG.Often there is evidence of thyroid autoimmunity (i.e., positive thyroid peroxidase antibodies), although this is not diagnostic.
Thyrotoxic phase of subacute thyroiditis
Associated with anterior neck pain and tenderness.
Absent or low uptake on I-123 scan, in contrast to generally normal uptake in toxic MNG.
Iodine-induced hyperthyroidism
History of an iodine load (from iodinated radiographic contrast, amiodarone, or a change in diet) in the setting of autonomous nodular thyroid disease (the Jod-Basedow phenomenon).
Low uptake on I-123 scan, in contrast to generally normal uptake in toxic MNG.24-hour urine iodine high.Thyroid blood flow on Doppler ultrasound may be increased. [16]
Functional thyroid cancer
Hyperthyroidism is only rarely caused by bulky metastatic follicular thyroid cancer.Thyroid cancer may cause hoarseness, and cervical lymph nodes may be palpable.
Total body scan shows radioactive iodine uptake over metastases.

Toxic shock syndrome

Gram-negative sepsis
Absence of desquamating rash.Renal failure more commonly develops subsequent to hypotension. [44]
Cultures positive for gram-negative organism (e.g., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa).
Rocky Mountain spotted fever (RMSF)
Severe headache and petechial rash are present in most patients.Rapid progression of disease.
Positive serology using indirect immunofluorescence assay detects increased IgM levels at the end of the first week of illness and increased IgG levels by 7 to 10 days after the onset of illness in RMSF.ELISA, latex agglutination, and dot immunoassays can also be used in the diagnosis of RMSF.
Acute meningococcaemia
Petechial rash, purpura, and meningitis may be seen.
CSF or blood culture with Neisseria meningitides.
Pneumonia
Symptoms of respiratory distress and crackles/rales on auscultation.
CXR shows infiltration, consolidation, effusions, and cavitation.Oximetry shows hypoxia and respiratory acidosis.
Meningitis
Headache and neck stiffness.
Positive CSF culture.
Leptospirosis
There may be no difference in signs and symptoms, although patients may be asymptomatic between phases of the disease.
Sensitivity of blood cultures is low, and culture isolation requires special media and up to 6 weeks of incubation.Indirect haemagglutination assay and IgM dot ELISA are specific for acute infections from leptospirosis. [76]
Heat stroke
Non-specific signs and symptoms such as fever, hypovolaemia, hypotension, confusion, and erythema can occur in both entities.
History of heat exposure is essential to the diagnosis.

Toxic thyroid adenoma

Graves' disease
Exophthalmos or pretibial myxoedema may be present.Onset and symptoms often more dramatic than for toxic nodule.
Thyroid scan shows diffuse uptake.Often there is evidence of thyroid auto-immunity (i.e., positive thyroid peroxidase antibodies), although this is not diagnostic.TSH receptor antibodies are positive, but rarely required for diagnosis.
Toxic multinodular goitre
Patients usually >40 to 50 years of age.Apathetic hyperthyroidism more likely, with weight loss, mood change or atrial fibrillation alone.
Scan shows areas of both increased and decreased uptake, indicating nonfunctioning and functioning nodules. [1] View image Uptake often normal.
Thyrotoxic phase of painless lymphocytic thyroiditis
Most often occurs post-partum.
Absent or low uptake on I-123 scan. Often there is evidence of thyroid auto-immunity (i.e., positive thyroid peroxidase antibodies), although this is not diagnostic.
Thyrotoxic phase of subacute granulomatous thyroiditis
Associated with anterior neck pain and tenderness.
Absent or low uptake on I-123 scan.ESR raised.
Iodine-induced hyperthyroidism
History of an iodine load (from iodinated radiographic contrast, amiodarone, or a change in diet) in the setting of autonomous nodular thyroid disease (the Jod-Basedow phenomenon).
Low uptake on I-123 scan.24-hour urine iodine high.
Marine-Lenhart's syndrome (nodular Graves' disease)
Exophthalmos or pretibial myxoedema may be present.
Thyroid scan shows diffuse uptake with a cold rather than hot area in the region of the palpable nodule. The nodule appears hot on scan only following treatment for Graves' disease. [22]
Functional follicular thyroid cancer
Very rare.There may be bulky metastatic disease or cervical lymphadenopathy.
Total body scan shows uptake of radioactive iodine over metastases.
Thyroidal haemiagenesis plus Graves' disease
Very rare.Exophthalmos or pretibial myxoedema may be present.
Ultrasound shows absence of the contra-lateral lobe. [23]

Toxoplasmosis

CNS lymphoma
There may be no difference in signs and symptoms, although fever may be less common.
Brain biopsy. Usually a solitary lesion.
Metastatic brain lesions from primary malignancy
There may be no difference in signs and symptoms.
Brain biopsy. Evidence of malignancy on physical examination or body imaging.
Mycobacterial CNS disease
Prior history of residence in an endemic area. May be history of chronic cough, weight loss, haemoptysis, and other signs of disseminated infection.
PCR of CSF for tuberculosis; mycobacterial culture of CSF; brain biopsy for acid-fast bacilli staining and culture; sputum stain and culture may be positive for acid-fast bacilli and CXR may show cavitations if pulmonary disease also present.
Aspergillosis
Presence of pulmonary lesions in addition to CNS lesions more frequently seen in aspergillosis. Symptoms may include cough, chest pain, and haemoptysis.
CSF fungal culture; galactomannan.
Cryptococcosis
Symptoms may include cough, chest pain, and haemoptysis.
Cryptococcal antigen from CSF and serum; CSF fungal culture.
Chagas disease
Prior history of residence in an endemic area (Central and South America). Acute infection is rarely symptomatic, but acute infection in the very young (<2 years old) may present with encephalitis or focal brain lesions, often accompanied by myocarditis, and poses a high mortality risk. Chronic infections occasionally develop acute CNS involvement (encephalitis with necrotic brain lesions causing mass effect) in immunocompromised patients.
Demonstration of Trypanosoma cruzi in blood, tissue or CSF; PCR of tissue or body fluids; serological tests.
Cytomegalovirus infection
Most common CNS opportunistic infection in AIDS patients, presenting subacutely with encephalitis, retinitis, progressive myelitis or polyradiculitis. In disseminated disease, may also include liver test abnormalities or worsening renal function.
Brain CT/MRI/biopsy: location of lesions are usually near the brainstem or periventricular areas.PCR of CSF with detectable virus is diagnostic.Brain biopsy with + staining for CMV or evidence of owl's eyes is also diagnostic, but is rarely performed because of the location of brain lesions.
Herpes simplex infection
Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only immunocompromised or acute infections in pregnant women; may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal. Neonatal HSV can range from localised skin infections to encephalitis, pneumonitis, and disseminated disease.
Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe.PCR of CSF with detectable virus is diagnostic.
Varicella zoster infection
Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke. Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis.
Disease is usually a vasculopathy, with haemorrhage and stroke.PCR of CSF with detectable virus is diagnostic.
Bacterial abscess (including Nocardia spp.)
May be associated with sinusitis (abutting the sinuses) or with bacteraemia. Signs and symptoms are similar, including fever and necrotising brain lesions with mass effect.
CSF culture or culture of brain abscess.
Progressive multifocal leukoencephalopathy (PML)
Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, and gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms.
PCR of CSF for JC virus.Biopsy reveals white matter lesions and not well-circumscribed lesions.

Tracheo-oesophageal fistula

Laryngeal cleft
These patients can present with symptoms similar to an H-type fistula with cyanotic spells, feeding difficulties, and recurrent chest infections.
This is best differentiated from a tracheo-oesophageal fistula by rigid bronchoscopy and oesophagoscopy.

Trachoma

Chlamydial inclusion conjunctivitis
Generally occurs in adults not living in areas where trachoma is endemic.
Swab culture detects genital strains of Chlamydia trachomatis.
Viral conjunctivitis
A common cause of conjunctival follicles.It can be distinguished from trachoma by an acute history and mucopurulent discharge.Herbert pits or pannus are absent.Both conditions may lead to tarsal conjunctival scarring.
A swab for HSV and adenovirus could be considered.
Bacterial conjunctivitis
Bacterial infection, such as Moraxella can be a rare cause of follicle formation.Absence of Herbert pits.
Microscopy, culture and sensitivity testing on a conjunctival swab may reveal a bacterial cause.
Hypersensitivity conjunctivitis
A careful history may reveal exposure to allergens (e.g., chronic exposure to drugs or eye cosmetics).Absence of Herbert pits.
If conjunctival swab is performed, the culture is negative for hypersensitivity conjunctivitis.
Vernal conjunctivitis
As an allergic disorder, patients often have associated atopy.Symptoms include itchiness, lacrimation, photophobia, foreign body sensation and burning.Absence of Herbert pits.
Giemsa cytology of conjunctival scrapings shows many eosinophils.
Parinaud oculoglandular syndrome
This rare ophthalmic condition may also cause follicles.There may be an associated condition such as cat-scratch fever, TB, syphilis, lymphogranuloma venereum, or glandular fever.Absence of Herbert pits.
Specific tests are required for each suspected associated condition, depending on history and clinical setting.
Trauma or chemical injury to eye
History of trauma or chemical contact with eye.Absence of Herbert pits.Both conditions may lead to tarsal conjunctival scarring.
No differentiating tests performed.
Stevens-Johnson syndrome
Other signs and symptoms typically include the sudden appearance of a rash or a rash appearing after a new medicine has been commenced.Both conditions may lead to tarsal conjunctival scarring.Absence of Herbert pits.Trachoma is more likely in an area where it is endemic.
No differentiating tests performed.
Ocular cicatricial pemphigoid
Pemphigoid has scarring in the bulbar conjunctiva and the plica; trachoma may show Herbert pits in the superior cornea.Both conditions may lead to tarsal conjunctival scarring.Trachoma is more likely in an area where it is endemic.
No differentiating tests performed.
Idiopathic trichiasis
May be difficult to differentiate clinically from trichiasis due to trachoma, although it is unlikely to have tarsal scarring.Absence of Herbert pits.Trachoma is more likely in an area where it is endemic.
Differentiated clinically.
Trichiasis due to other chronic inflammatory conditions
Trichiasis can be idiopathic or secondary to a large range of chronic inflammatory diseases such as blepharitis and chronic conjunctivitis.Absence of Herbert pits.Trachoma is more likely in an area where it is endemic.
No differentiating tests performed.
Corneal opacity due to other causes
There are many other causes of corneal opacity.However, when seen in conjunction with trichiasis and other signs of trachoma in a patient who has spent a significant amount of their life in a trachoma-endemic area, a diagnosis of trachomatous corneal opacity is likely.
No differentiating tests performed.

Transfusion reaction

Transfusion-associated sepsis
Clinically difficult to distinguish from immune-mediated transfusion reaction.
Direct antiglobulin test, inspection of plasma specimen rule out haemolysis.Gram stain may be positive.Blood culture from patient and remainder of blood transfusion component may grow culprit organism. Caused by bacterial contamination of transfused component.Associated with platelets (bacterial contamination in 1/1000 to1/2000 units) more than other transfused components. [20] [21]
Non-immune-mediated haemolysis
Occurs rarely.Presents acutely, with haemoglobinuria (red urine).
Direct antiglobulin test is usually normal, differentiating this from immune-mediated haemolysis.This, along with inspection of plasma specimen and repeat patient blood-typing, rules out immune-mediated patient haemolysis.Component should be evaluated for haemolysis. Caused by mechanical destruction of red cells as a result of improper storage temperatures, inappropriate syringe size, or damage from roller pumps. Transfusion blood should be transfused with normal saline. Hypotonic fluids such as D5W cause osmotic haemolysis of red cells. Uncommonly, patients receive blood from donors with pre-existing red-cell membrane disorders that are predisposed to haemolysis, triggering a reaction similar to an immune haemolytic reaction.
Transfusion-associated circulatory overload
Findings of volume overload such as jugular venous distension.
Differentiation from transfusion-related acute lung injury (TRALI) requires determination of whether pulmonary oedema is cardiogenic (overload) or non-cardiogenic (TRALI). Elevated brain natriuretic peptide, central venous pressure, or pulmonary artery wedge pressure suggest volume overload.

Transient ischaemic attack

Hypoglycaemia
Most commonly seen in a patient who takes hypoglycaemic medications.Can cause syncope, generalised weakness, or confusion, but also is reported to cause focal deficits, especially if old cerebral insults are present.
Blood glucose <3.33 mmol/L (<60 mg/dL).
Seizure with Todd's paralysis
One of the most frequent mimics of cerebral ischaemia.Patients will frequently have pre-existing epilepsy.Witnesses will report positive motor symptoms (such as tonic-clonic activity) prior to onset of weakness.Symptoms may have 'Jacksonian march' across the affected area.Incontinence, tongue biting, and post-event altered mental status suggest seizure rather than TIA.
The distinction is frequently made based on the clinical history.EEG can be done to evaluate for seizures or for postictal slowing.Elevated prolactin level has a secondary role to suggest seizure.
Complex migraine
Usually occurs in patients with prior history of migraine headaches.Aura or scotomata may precede onset of weakness.Presence of headache and nausea along with neurological symptoms suggest complex migraine.
Clinical diagnosis: no differentiating tests.
Space-occupying lesion (intracranial haemorrhage, abscess, or mass)
Preceding trauma or anticoagulation predisposes to haemorrhage.Fever or leukocytosis would suggest CNS infection rather than ischaemia.Headache and vomiting may occur with increased intracranial pressure.May have a relatively gradual onset compared with ischaemic neurological deficits.Rapid complete resolution of symptoms would be atypical of an irreversible structural lesion.
Non-contrast head CT rules out presence of acute haemorrhage.CT with contrast or MRI can be done if continued suspicion for CNS abscess or mass.Elevated WBC count in an infection.
Conversion disorder/panic attack
Deficits may not fit a single vascular territory.Physical examination may demonstrate inconsistencies such as demonstrating 'breakpoint' weakness.Prior history of psychiatric illness or major psychosocial stressor raises suspicion.
Clinical diagnosis: no differentiating tests.
Labyrinthine disorders
Benign positional vertigo may be mistaken for posterior circulation infarct.Hearing loss and tinnitus suggest Meniere's disease.Labyrinthitis can cause vertigo and disequilibrium but motor function and other cranial nerves should be normal.
Clinical diagnosis: no differentiating tests.
Multiple sclerosis (MS)
New MS lesions or a pseudoexacerbation might be mistaken for TIA, but MS will tend to cause reversible neurological deficits lasting longer than those of TIA.
MRI can reveal MS plaques.Lumbar puncture in MS may demonstrate pleocytosis and oligoclonal bands.
Peripheral neuropathy
Bell's palsy may be mistaken for ischaemic insult. Unlike central ischaemia, Bell's palsy does not spare the forehead.Peripheral neuropathies with the exception of transient compression neuropathy tend to last longer than 24 hours.
For peripheral neuropathy with transient symptoms, no testing is generally needed.
Global hypoperfusion/syncope
Syncope caused by basilar TIA is almost always associated with focal neurological signs/symptoms in addition to the syncope itself.Systemic illness is suspected based on fever, tachycardia, or hypotension.Hypotension may mimic TIA, particularly by causing pre-existing CNS injuries such as MS plaques or old strokes to have more pronounced symptoms.BP may be low or orthostatic vital signs may be positive in the patient with hypotension as cause of syncope/weakness.
If underlying infection, may have an elevated WBC count.

Transient synovitis of the hip

Septic arthritis
Pain is more severe, and the child often cannot walk. Any hip motion is painful, even through a small arc of motion.Destruction of the articular cartilage begins quickly and is secondary to proteolytic enzymes and impairment of intra-capsular vascular supply.A delay in treatment can have devastating consequences, with near-total destruction of the hip, for which there are no good reconstructive options.
Four independent clinical predictors have been identified to differentiate between septic arthritis and transient synovitis: fever >38.5°C (>101.3°F), non-weight-bearing, ESR >40 mm/hour, and serum WBC count >12,000 cells/mm^3. The predicted probability of septic arthritis was summarised as <0.2% for zero predictors, 3.0% for 1 predictor, 40% for 2 predictors, 93.1% for 3 predictors, and 99.6% for 4 predictors. [6]When this paradigm was applied prospectively by either the same institution or others, the predicted probability did decrease, but its use as a clinical indicator is still extremely helpful. [7] [8]If joint aspiration is performed, white cell count >25,000 per high power field would suggest that septic arthritis is likely.
Lyme arthritis
A late manifestation of Lyme disease, it usually manifests as monoarticular or oligoarticular arthritis, commonly involving large joints. Large knee effusions are common, usually resolving in a few weeks to a few months if untreated.
Serology can confirm previous history of Lyme disease.
Osteomyelitis
Osteomyelitis of the hip presents with hip pain. The child may appear ill, have a fever, and have pain with ambulation. Joint motion will be less restricted.Osteomyelitis of the pelvis would present with hip or pelvic pain. Acute pain with hip motion should be less significant.
X-ray may show bony changes if late in the disease process: for example, periosteal elevation and cortical or medullary lucencies. MRI will demonstrate increased signal intensity on the T2 images in the femoral head and metaphysis early in the disease process, and has been shown to be a reliable method to assess the periarticular bone for osteomyelitis.
Legg-Calve-Perthes disorder
Children, more commonly boys, will present typically with a limp that occurs over weeks to months.
Early x-rays may show only subtle signs of joint space widening; more obvious signs, such as femoral head collapse, will be evident weeks to months later. Labs will be normal.
Pyogenic sacroiliitis
This would typically present with pain and/or tenderness over the SI joints.
An MRI of the pelvis would show changes in the SI joint, such as increase in T2 signal intensity.
Juvenile idiopathic arthritis
For a diagnosis to be made the child must have had objective arthritis in the joint for at least 6 weeks. There may be stiffness on waking or after periods of inactivity.In certain sub-types the child may have a spiking fever, a salmon-coloured rash over the trunk and proximal extremities, uveitis, and rheumatoid nodules on extensor surfaces of tendons.
Diagnosis is predominantly based on clinical signs and symptoms. Laboratory tests such as ESR, CRP, ANA, and RF are mainly used to determine the sub-type. Imaging of the joints involved may aid diagnosis but is not specific. X-rays are usually normal in early disease but may be used to monitor disease activity.

Transverse myelitis

Compressive myelopathy
Known history of cancer or recent trauma are risk factors. [49] [50] Epidural abscess may be associated with known infection (e.g., TB) or fever. Compressive haematoma may occur in anticoagulated patients. However, clinical features of the myelopathy are indistinguishable from TM.
Spinal cord MRI with gadolinium.
Infectious myelitis (e.g., tuberculosis)
May have systemic infectious syndrome.
Specific tests for individual infections are positive.
Anterior spinal artery occlusion
Anterior cord syndrome (paraparesis, sensory level, and sparing of posterior column dysfunction).History of aortic surgery, intra-operative hypotension, vasculitis, spinal angiography, systemic emboli, prothrombotic state. [51]
Spinal cord MRI: thin linear lesion restricted to anterior two-thirds of the spinal cord cross-sectional area.
Posterior spinal artery occlusion
Posterior column syndrome (impaired vibratory and proprioceptive functions).History of aortic surgery, intra-operative hypotension, vasculitis, spinal angiography, systemic emboli, prothrombotic state. [51]
Spinal cord MRI shows focal lesion restricted to posterior one third of the cord cross-sectional area.
Arteriovenous fistula
Progressive myelopathy with step-wise deterioration; sometimes with positional features such as increased symptoms with walking or with Valsalva manoeuvre; combined upper and lower motor neuron syndrome. [52]
Spinal cord MRI shows a long or patchy cord lesion, with or without cord swelling; heterogeneous gadolinium enhancement; presence of tortuous vessels on dorsal cord surface.Spinal angiography confirms diagnosis.
Haematomyelia
Known coagulopathy, anticoagulation, or vascular lesion such as cavernoma.
MRI spinal cord: signal change consistent with blood products, appearance changes over time (acute compared with subacute or chronic).
Neoplastic myelopathy
Known history of cancer is risk for intramedullary metastases.Tumour infarction or haemorrhage may present acutely and mimic TM.Primary tumours usually present as a subacute to chronic myelopathy without distinguishing clinical features. [49]
MRI spinal cord shows irregular, heterogeneous, and enhancing cord lesion.Persistent gadolinium enhancement lasting for several months.Spinal cord biopsy confirms diagnosis.
Radiation myelopathy
History of radiotherapy where field included spinal cord.Usually presents as a delayed progressive myelopathy with cord atrophy but occasionally is subacute. [53]
Spinal cord MRI shows cord atrophy and increased T2 signal in adjacent vertebrae in chronic cases.Subacute lesions may mimic inflammatory TM but vertebrae are usually abnormal.EMG reveals myokymia in weak muscles.
Paraneoplastic myelopathy
Sometimes known history of cancer.May present as a 'tractopathy' with clinical features restricted to, for example, corticospinal tracts. [19] [54]
MRI spinal cord may reveal bilateral, symmetric, and enhancing signal abnormality restricted to anatomical long tracts.Positive paraneoplastic antibody panel for antibodies such as amphiphysin, collapsin response mediated protein (CRMP)-5, antineuronal nuclear antibody (ANNA)-2, neuronal acetylcholine receptor antibodies, P/Q or N-type calcium channel antibodies, voltage-gated potassium channel antibodies, Purkinje's cell antibodies, or glutamic acid decarboxylase (GAD) antibodies.Discovery of occult tumour with body imaging (CT, MRI, or PET).
Fibro-cartilaginous embolism
Sudden deficit associated with physical exertion, spine pain, and anterior spinal artery syndrome. [55]
Spinal cord MRI shows a cord signal abnormality with adjacent loss of intervertebral disc height and end-plate micro-fractures.
Cerebral lesion
Headache for some causes such as hydrocephalus, stroke (arterial or venous).
MRI brain confirms diagnosis.
Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome)
Subacute flaccid weakness with hyporeflexia or areflexia, paraesthesia but little or no demonstrable sensory impairment. [56]
MRI spinal cord negative; may reveal enlarged and enhancing spinal roots.CSF shows elevated protein but normal WBC.EMG demonstrates peripheral abnormalities.
Plexopathy
Subacute lower extremity pain, weakness and sensory symptoms, usually asymmetric; diabetic patients or those with metastatic cancer.
MRI spinal cord negative.MRI lumbosacral plexus may show nerve enhancement or nodularity consistent with metastases.EMG demonstrates peripheral abnormalities.
Motor neuron disorder
Chronic, progressive painless weakness without sensory symptoms or bladder involvement; mixed upper and lower motor neuron signs.
Negative spinal cord MRI.Characteristic clinical examination and EMG findings.
Myasthenia gravis
Fatigable weakness without pain, sensory symptoms, or autonomic involvement.
Positive acetylcholine receptor antibodies, positive edrophonium test, abnormal EMG.
Copper deficiency
Patient at risk for nutritional deficiency based on diet, medical disease, or surgery (especially bariatric/gastric surgery). [57]
Low serum copper level.
Vitamin B12/folate deficiency
Patient at risk for nutritional deficiency (e.g., bariatric/gastric surgery).History of nitrous oxide inhalation abuse.Painless weakness, ataxia, and sensory symptoms.
Low serum B12 level, macrocytic anaemia, elevated serum homocysteine and methylmalonic acid levels, history of recent nitrous oxide exposure, MRI spinal cord may show lesion in dorsal columns and/or corticospinal tracts.

Traveller's diarrhoea

Irritable bowel disease
Alternating constipation and/or diarrhoea worse under stress (no weight loss, fever, or systemic symptoms).
Normal examination, and laboratory and bowel work-up.
Pseudomembranous (Clostridium difficile) colitis
Persisting diarrhoea with weight loss often following use of antibiotics (with or without travel history).
C difficile stool toxin positive; colonoscopy demonstrates pseudomembranes.
Coeliac disease
Persisting diarrhoea with malabsorption (with or without travel history).May be associated with dermatitis herpetiformis.
AGA (IgA anti-gliadin antibodies), EMA (IgA anti-endomysium antibodies), AGG (IgG anti-gliadin antibodies), tTGA (IgA anti-tissue transglutaminase) may be positive.Since IgA deficiency may interfere with coeliac testing, an IgA level should also be obtained.
Crohn's disease
Diarrhoea (with or without travel history), abdominal pain, fever, perianal fistulae.
Elevated sedimentation rate, elevated faecal calprotectin, anaemia, haem-positive stools. Colonoscopy differentiates most cases of Crohn's disease from ulcerative colitis. Ulcerative colitis always involves the rectum and is contiguous versus intermittent. Crohn's disease often has perianal involvement, rectal sparing, and a tendency to form fistulae.
Ulcerative colitis
Bloody diarrhoea (with or without travel history), abdominal pain, fever, no perianal disease.
Elevated sedimentation rate, elevated faecal calprotectin, anaemia, haem-positive stools. Colonoscopy differentiates most cases of Crohn's disease from ulcerative colitis. Ulcerative colitis always involves the rectum and is contiguous versus intermittent. Terminal ileitis may be present in ulcerative colitis with pancolitis due to backwash.
Food poisoning
Predominant symptom is vomiting.It is easy to confuse the symptoms of TD with those of food poisoning; the latter is of much earlier onset and is characterised more by vomiting than by diarrhoea (excepting Clostridium).Food poisoning, while self-limited, does not respond to antibiotics.Staphylococcus aureus and Bacillus cereus (both forming heat-stable toxins) or C perfringens (heat-labile toxins) cause most food poisoning cases.Pre-formed toxins (from Staphylococcus or Bacillus) produce symptoms (vomiting > diarrhoea) within 1 to 6 hours, whereas Clostridium infections, with in vivo toxin formation, cause diarrhoeal symptoms within 8 to 16 hours. Most TD bacterial infections, on the other hand, become symptomatic 16 hours after ingestion. [5]
Typically diagnosed clinically, but bacterial cultures or virological studies may elicit culprit organism.

Trichinellosis

Gastroenteritis
More prominent watery or bloody diarrhoea.If systemic manifestations are present, they usually occur concomitantly with the gastrointestinal manifestations, rather than following them.
Stool sample: cultures positive for Salmonella, Shigella, or Campylobacter; presence of white cells or lactoferrin.
Respiratory or gastrointestinal viral infections
Myalgia and fever are common, but are usually associated with other respiratory (cough, coryza) or gastrointestinal (vomiting, diarrhoea) manifestations.Outbreaks of viral infections are more common and widespread than those of trichinellosis.
Viral antigens and cultures: positive in nasopharyngeal and bronchial samples in respiratory infections; positive in stool sample in gastrointestinal infections.
Glomerulonephritis
In addition to fever, eosinophilia, and peri-orbital oedema, this condition causes haematuria and/or proteinuria, and renal failure.
Urinalysis: presence of protein, blood, leukocytes, RBC casts, and dysmorphic RBCs.Serum creatinine: elevated.Urea: elevated.Kidney biopsy: shows inflammation, cellular proliferation, basement membrane thickening, fibrosis, and epithelial cell changes, and is confirmatory.
Anaphylaxis
Hyper-acute presentation.Peri-orbital oedema is normally accompanied by swelling of other mucosae (angio-oedema), hives, and possible respiratory distress.
There are no confirmatory diagnostic tests.Diagnosis is based on the clinical presentation and presence of a trigger factor.
Polymyositis and dermatomyositis
Clinical course is more chronic.Symmetric proximal muscle weakness is more common than myalgia.Peri-orbital oedema may occur, but the rash in dermatomyositis is not transient.
EMG: short-duration, low-amplitude poly-phasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves.Muscle biopsy: shows lymphocytic infiltrates, fibre atrophy, and necrosis, and (with electromyography results) is confirmatory.Auto-antibodies: ANA, anti-Jo-1 antibodies, anti-SRP antibodies, and antibodies to Mi-2 may be positive.
Peri-orbital cellulitis
Eyelids are red and painful.Fever may be present, but there is no myalgia.
There are no confirmatory diagnostic tests.Diagnosis is usually clinical.Blood cultures may occasionally be positive.
Parasitoses
Several helminthic infections such as schistosomiasis, toxocariasis, and fascioliasis cause eosinophilia and may be confused with trichinellosis in the early stages.
Stool sample: presence of ova or parasite.Serum antibodies: may be positive for each specific parasite.
Infective endocarditis
Causes fever (more persistent than in trichinellosis), myalgia, and splinter haemorrhages.Cardiac murmur is invariably present.Other embolic or immune manifestations may be present.
Echocardiogram: mobile vegetations on heart valves.Blood cultures: positive.
Eosinophilia-myalgia syndrome
Eosinophilia, myalgia, and cutaneous manifestations (rashes, pruritus) are common.May occur in outbreaks and is usually associated with the consumption of L-tryptophan.
There are no confirmatory diagnostic tests.
Leptospirosis
Bi-phasic disease beginning with fevers, myalgia, rash, and gastrointestinal manifestations after contact with animal urine or faeces.Followed by second phase with meningitis, liver, and renal failure.
Blood cultures: positive for Leptospira species.ELISA: positive for antibodies against Leptospira species.PCR: positive for Leptospira species.

Tricuspid stenosis

Cardiac tumours
There are no specific differentiating signs/symptoms.
Echocardiogram will often show tumours and differentiate cause.
SLE
Malar rash, arthritis/arthralgias, pancytopenia, photosensitivity, renal involvement, alopecia, or Raynaud's phenomenon.
ANA, anti-dsDNA or anti-Sm antibodies may be positive in SLE.
Constrictive pericarditis (CP)
Usually have a previous history of tuberculosis, pericarditis, cardiac surgery, mantle radiation, chest trauma, or connective tissue disease. Murmurs are rare with CP and jugular venous pulsations are less prominent.
Calcification of pericardium sometimes seen on CXR.Echocardiogram shows only mildly enlarged atrium and normal tricuspid valve without a gradient.Cardiac catheterisation reveals absence of tricuspid valve gradient and classic haemodynamic findings of CP.
Restrictive cardiomyopathy
History is usually unremarkable. Systolic murmurs of mitral and tricuspid regurgitation are most common. Diastolic murmurs are less common. Jugular venous pulsations can be prominent.
Echocardiogram shows severe bi-atrial enlargement in the absence of significant AV valve gradient. Valve can sometimes be thickened, but shortened chordae and commissural fusion are rarely discovered.Cardiac catheterisation reveals classic findings of restrictive cardiomyopathy without tricuspid valve gradient.

Tricyclic antidepressant overdose

Overdose of sodium channel blockers
The history of suicidal overdose is often the same. History of use of sodium channel blockers: e.g., class 1a antiarrythmics (quinidine, procainamide, disopyramide), class 1c antiarrythmics (flecainide, propafenone), and local anaesthetics.The degree of toxicity is often the only clue to the diagnosis of TCA overdose as these patients tend to be more seriously ill and decline more rapidly.
No specific diagnostic test. Differentiating among these sodium channel blockers is often difficult. Response to sodium bicarbonate therapy may also be similar. They may produce diagnostic ECGs that appear comparable.
Conditions causing right axis ECG deviation
With bronchospasm or large pulmonary embolus, no anticholinergic signs are present.Structural heart disease is not associated with anticholinergic signs either.
In the case of bronchospasm or a large pulmonary embolus, sinus tachycardia should be present but not QRS prolongation.Healthy children may also have persistent right ventricular forces, which produce a similar axis shift without QRS widening.Consider other clinical parameters to differentiate these diagnoses. In these conditions, patients do not respond to sodium bicarbonate therapy.
Anticholinergic overdose
The signs and symptoms produced by all agents are similar. Examples include atropine and antihistamines (e.g., diphenhydramine), antipscyhotics, and antispasmodics. Again, a seriously ill and rapidly declining patient may be the only clue that a TCA is involved.
No specific diagnostic test. As with differentiating among sodium channel blockers, differentiating among potential anticholinergics becomes difficult.

Trigeminal neuralgia

Dental caries
Well localised to a single tooth.
Intra-oral x-rays.
Dental fracture
Localised to ≥1 teeth; may be provoked by biting.
Intra-oral x-rays.
Mandibular osteomyelitis
Typically continuous pain along mandible with associated swelling. History of fever, malaise, purulent discharge, mobile teeth.
Intra-oral x-rays.
Temporomandibular joint syndrome
Often bilateral, jaw opening may be restricted.
No differentiating tests.
Migraine
Presence of preceding aura. Associated with photophobia, nausea.
No differentiating tests.
Glossopharyngeal neuralgia
Pain is in the distribution of the glossopharyngeal nerve, classically oropharyngeal and otic.
No differentiating tests.
Post-herpetic neuralgia
Typically presents as continuous pain in distribution of upper division of trigeminal nerve (V1). Patient often has tactile allodynia.
No differentiating tests.
Temporal arteritis
Pain is often continuous, can be bilateral, and may be associated with jaw claudication, visual changes, and anorexia.
ESR, temporal artery biopsy (gold standard).
Atypical facial pain
Often is bilateral and/or exceeds the confines of a trigeminal distribution.
Diagnosis is made with formal neuropsychological evaluation.
Trigeminal autonomic cephalgias (e.g., cluster headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing [SUNCT] syndrome, chronic paroxysmal hemicrania)
Often have prominent autonomic features (e.g., conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, ptosis). Pain associated with cluster headaches, typically retro-orbital. [21]
No differentiating tests.

Tropical sprue

Parasitic infections: Strongyloides, Isosporiasis, Giardia lambia, Entamoeba histolytica
Parasitic infections often presents with the same signs and symptoms as tropical sprue (TS).Malabsorption in TS is generally more profound and typically involves micro-nutrients such as folate.
Stool microscopy may reveal ova and parasites.Stool and/or serum antigen testing for specific parasites may be positive.Giardiasis may feature some degree of villous blunting in the proximal small bowel as seen in TS; other infections do not.
Bacterial infections: Shigella, Salmonella, Escherichia coli
Bacterial infections typically lead to an acute presentation.GI and constitutional symptoms such as diarrhoea, abdominal pain, and fever are more severe.Diarrhoea may be bloody, which is not seen in TS.
Stool should be cultured for the presence of these micro-organisms.
HIV enteropathy
Chronic diarrhoea, weight loss, abdominal cramps, anal pain, fevers.Diffuse abdominal tenderness, hepatosplenomegaly, lymphadenopathy.
HIV test is positive.Can mimic the histological small-bowel findings that are seen in TS.
Tuberculosis
Can closely mimic the clinical signs and symptoms of TS.Features of systemic disease may be present.
Staining for mycobacterium of bowel tissue positive.Blood, biopsy, or sputum samples may show mycobacterial infection.Can mimic the histological small bowel findings that are seen in TS.
Whipple's disease
Can closely mimic the clinical signs and symptoms of TS.Arthralgia/adenopathy may be present.
Small-bowel biopsy may culture periodic acid-Schiff-positive macrophage inclusions.
Small-bowel lymphoma
In immunoproliferative small intestinal disease (IPSID), GI/constitutional symptoms such as abdominal pain, fever, and chills predominate over features of malabsorption.
Small-bowel biopsy may be histologically distinguishable.
Crohn's disease
Profound malabsorption not commonly seen. Bloody diarrhoea common.Disease course waxes and wanes while TS more commonly features an indolent progression.
Colonoscopy with intubation of the terminal ileum may reveal macroscopical features (gross mucosal erythema and ulceration) not seen in TS.Abdominopelvic CT and/or upper GI series with small bowel follow may reveal strictures and fistulae.
Coeliac sprue (CS)
More commonly affects white people of European descent.No acute period of diarrhoea with CS.
IgA antibodies positive in CS.Anti-endomysial antibodies should also be positive.Biopsies indistinguishable.Therapeutic trial of folic acid: TS responds.Gluten-free diet: CS responds.
Scleroderma
Upper GI symptoms such as heartburn and dysphagia more common.Features of malabsorption unlikely unless concomitant small-intestinal bacterial overgrowth present.Likely to manifest classic skin changes; evidence of interstitial lung disease and renal involvement common.
Antinuclear antibodies are present in about 95% of patients.Topoisomerase I antibodies and anticentromere antibodies often present in limited disease.
Small-intestinal bacterial overgrowth
Can complicate altered intestinal anatomy (e.g., blind loops following surgery), scleroderma, or disordered intestinal motility, as well as patients with no underlying disorders.Features of malabsorption, particularly folic acid deficiency, not as common as in TS.
No villous atrophy on small-bowel biopsy as is seen in TS.No evidence of multiple micro- and macro-nutrient deficiencies as seen in TS.
Pancreatic insufficiency
Often manifests signs/symptoms of malabsorption including diarrhoea, steatorrhoea, and fat-soluble hypovitaminosis, but signs/symptoms of protein, carbohydrate, folic acid, and vitamin B deficiencies not present.
No evidence of megaloblastic anaemia, abnormal D-xylose testing, or hypoproteinaemia.
Tropical enteropathy (TE)
Closely resembles TS; often viewed as a sub-clinical form of the disease.TE found in same endemic areas.Associated with the malabsorption of multiple micro- and macro-nutrients.Rarely causes the symptoms that typify TS.TE does not respond as predictably to treatment with folic acid and antibiotics.Malabsorption seen in TE resolves after 6 to 12 months spent in temperate climate.
No differentiating tests.

Tuberous sclerosis complex

Periventricular nodular heterotopia (PNH)
Skin, ophthalmological, and general examination is normal.There are no cutaneous features or other organ involvement. [21] [22]Inheritance pattern is as an X-linked dominant or sporadic condition.
Affected people present with seizures, and neuroimaging discloses periventricular nodules consistent with heterotopia. These nodules do not have calcification.There may be additional brain dysgenesis distinct from TSC.Genetic testing for FLMN and HEX1 genes may yield mutations consistent with PNH. [21] [22]
Multiple endocrine neoplasia (MEN-1)
Facial angiofibromas can be seen in about 80% of MEN-1 patients. [17] Other hallmark dermatological and neurological clinical features of TSC are not identified.This is an autosomal-dominant disorder with a propensity for parathyroid and pancreatic islet cell tumours, among other features. [23]
Genetic mutations in the MEN-1 gene reside at chromosome 11q13. [17]

Tularaemia

Tularaemic bacteraemia
No differentiating signs or symptoms.
Positive culture for Francisella tularensis.
Cat scratch disease
Localised lymphadenopathy with a scratch.
Positive serology for Bartonella henselae.
Toxoplasmosis
Bilateral lymphadenopathy and fever.
Positive IgM serology for Toxoplasma gondii.
Non-tuberculous mycobacterial infections
Unilateral sub-mandibular lymphadenopathy.
Excisional biopsy of the node and culture of mycobacterium.
Infectious mononucleosis
Diffuse lymphadenopathy.
Positive monospot test.
Plague
Unilateral lymphadenopathy.
Positive culture for Yersinia pestis.
HIV
Diffuse lymphadenopathy.
HIV positive serology.
Community-acquired pneumonia
No differentiating signs or symptoms.
Sputum and blood cultures can diagnose some of the common causes.Special media and urine antigen are useful for the diagnosis of legionella pneumonia.PCR, antigen detection, and culture of respiratory secretions are all useful tests for pneumonia due to viral aetiologies.
Streptococcal pharyngitis
Exudative pharyngitis.
Throat swab bacterial cultures and rapid test for group A streptococci (Streptococcus pyogenes) would be positive in most cases.
Conjunctivitis
No differentiating signs or symptoms.
Bacterial and viral causes of conjunctivitis can be cultured, and the Acanthamoeba identified by its characteristic microscopic appearance.

Tumour lysis syndrome

Isolated hyperuricaemia
Also associated with malignancy, particularly haematological tumours. [10] [28] [29]May be asymptomatic or present with nephrolithiasis or gout.
Serum potassium, phosphate, and calcium levels are normal.
Isolated hyperkalaemia
Can present with fatigue, weakness, paraesthesia, palpitations, or life-threatening arrhythmias. Patient may be taking potassium-sparing medication, systemic heparin, or non-steroidal anti-inflammatory drugs. Renal failure and frequent blood transfusions can contribute. [30]
Serum uric acid, phosphate, and calcium levels are normal.
Isolated hyperphosphataemia
History of dehydration and volume depletion, pulmonary embolism, bone metastases, or advanced renal failure. [30] Use of bisphosphonates, laxatives, and antacids may contribute. Symptoms such as tetany and cramping relate to hypocalcaemia caused by hyperphosphataemia.
Serum uric acid, potassium, and calcium levels are normal.
Isolated hypocalcaemia
Perioral numbness or tingling, paraesthesia of hands and feet, positive Trousseau or Chvostek sign.
Serum uric acid, phosphate, and potassium levels are normal.

Turner's syndrome

Constitutional delay of growth and development
Short girls aged 12 to 15 years may have pubertal delay due to the benign condition known as constitutional delay.No associated dysmorphic features or congenital defects.
A clinical diagnosis primarily and investigations are typically negative.Bone age is slightly delayed.Cytogenetic testing is required rarely and is normal.
Noonan's syndrome
Distinguishing features are hypertrophic cardiomyopathy and pulmonic stenosis, triangular facies, prominent chest wall deformity, and mental retardation, which are not common in Turner's syndrome.Can occur in phenotypic males and females.
Normal karyotype.Several genes have been implicated in this autosomal dominant disorder.
46,XX gonadal dysgenesis
Unknown genetic defects in ovarian development.Present with primary amenorrhoea.No dysmorphic features typical of Turner's syndrome.No short stature or congenital heart defects.
Karyotype is normal female 46,XX.

Type 1 diabetes

Maturity onset diabetes of the young (MODY)
Strong family history.Slow onset.Absence of ketoacidosis.Response to sulphonylurea drugs.
C-peptide present.Anti-glutamic acid decarboxylase (GAD) antibodies absent.
Type 2 diabetes
Typically, signs of insulin resistance (such as acanthosis nigricans) should be sought and in their absence clinical suspicion of type 1 diabetes is greater.Signs of more marked insulin deficiency (for example, glycaemic lability as well as susceptibility to ketosis) raise suspicion of type 1 diabetes.Older age and slow onset, obesity, a strong family history, absence of ketoacidosis, and initial response to oral anti-hyperglycaemic drugs are typical of type 2 diabetes.
C-peptide present.Anti-glutamic acid decarboxylase (GAD) antibodies absent.Testing for C-peptide and GAD usually not required.

Type 1 neurofibromatosis

Neurofibromatosis type 2 (NF2)
Bilateral vestibular schwannomas, intracranial meningiomas and/or ependymomas, spinal glioma, paraspinal schwannomas, cutaneous schwannomas, posterior subcapsular cataracts, pigmentary retinopathy, absence of typical cafe au lait spots. [15]
Identification of a mutation at the NF2 locus in chromosome band 22q11. [16]
McCune-Albright's syndrome
Very few or no cafe au lait spots, no axillary freckling, polyostotic fibrous dysplasia. [17]
Identification of an activating mutation in the GNAS1 gene locus in chromosome band 20q13.2.
Familial cafe au lait spots
Absence of other features with NF1, even though the number of cafe au lait spots might suggest NF1. [1] [18]
Absence of an NF1 mutation.
NF1-like syndrome
Absence of neurofibromas or optic pathway glioma or other features of NF1 except for the presence of cafe au lait spots, axillary freckling, macrocephaly, facial dysmorphism, and perhaps learning difficulties. [19]
Identification of a mutation in the SPRED1 gene in chromosome band 15q13.2.
Proteus syndrome
Localised overgrowth superficially mimicking ≥1 large diffuse plexiform neurofibromas in the absence of other features of NF1. [20] [21]
Absence of an NF1 mutation.
Age-related cutaneous neurofibromas
One to several cutaneous neurofibromas that do not buttonhole (i.e., push deeper into the dermis when pressed) and appear only in or beyond the fifth decade of life. [1]
Absence of an NF1 mutation in a non-neurofibroma specimen.
Isolated diffuse plexiform neurofibroma
A diffuse plexiform neurofibroma in the absence of any other features of NF1. [1]
Absence of an NF1 mutation in a non-neurofibroma specimen.

Type 2 diabetes in adults

Diabetes mellitus, type 1
Onset often at age <35 years, but can occur in older individuals.Many patients are not obese.
Urine ketones are often present in type 1 diabetes, but may be positive in type 2 diabetes if there is severe volume depletion.Anti-glutamic acid decarboxylase (GAD) antibodies, islet cell antibodies, and insulin autoantibodies are present in 85% of patients with type 1 at the time of diagnosis, but may disappear within a few years. Usually not required for diagnosis.Glucose criteria cannot be used to differentiate type 1 and type 2 diabetes, as they are identical.
Pre-diabetes
Patients with pre-diabetes often have no specific differentiating signs or symptoms.
Fasting plasma glucose level is 5.6 mmol/L to 6.9 mmol/L (100-125 mg/dL) in pre-diabetes.2-hour post-load glucose after 75 g of oral glucose is 7.8 mmol/L to 11.0 mmol/L (140-199 mg/dL) in pre-diabetes.HbA1c of 5.7% to 6.4% indicates pre-diabetes or high risk of future diabetes. [2]
Maturity onset diabetes of the young (MODY)
Onset often in childhood or adolescence. Insulin treatment usually required.
No differentiating tests.
Diabetes, gestational
This only occurs during pregnancy.
Gestational diabetes is detected by screening during pregnancy.The 2011 American Diabetes Association recommendations, [2] based on the HAPO study, [20] are now to test all women not previously known to have diabetes using the 75 g oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation, and using diagnostic cut points of ONE or more abnormalities: fasting ≥5.1 mmol/L (≥92 mg/dL); 1-hour ≥10.0 mmol/L (≥180 mg/dL); or 2-hour ≥8.5 mmol/L (≥153 mg/dL).This change in screening test will likely increase the prevalence of gestational diabetes from about 8% to about 18% to 20% of pregnancies in the US. The new guidelines also call for testing all pregnant women with risk factors for type 2 diabetes at the first neonatal visit, although a diagnosis at this stage would be considered a diagnosis of type 2 diabetes and not gestational diabetes. [2]

Type 2 diabetes in children

Glucose intolerance
There may be no differentiating symptoms.
Fasting glucose is between 5.6 and 6.9 mmol/L (100 to 125 mg/dL).Two-hour post-load glucose is 7.8 to 11 mmol/L (140 to 199 mg/dL) on oral glucose tolerance test.HbA1c of 5.7%-6.4%.
Type 1 diabetes mellitus (T1DM)
Most patients with T1DM are not obese and have a short duration of symptoms, with recent polyuria, polydipsia, and weight loss, symptoms that are not common in type 2 diabetes mellitus (T2DM).Typically, there is no family history.
Urine ketones are often present in T1DM but observed in only 15% of children with T2DM.Antibodies to insulin, islet cell, glutamic acid decarboxylase, or ZnT8 are present in 85% to 98% of individuals with T1DM but are typically negative in T2DM.
Monogenic diabetes
Formerly known as maturity-onset diabetes of youth (MODY).Heterogenous group of autosomal-dominant disorders due to defects in beta-cell function resulting in insulinopenic diabetes before the age of 25 years.There may be no differentiating symptoms.
No differentiating tests.In the absence of symptoms, diagnosis is also made due to the presence of hyperglycaemia after an oral glucose tolerance test.Specific genetic testing available.
Atypical diabetes of black youth
Usually presents with ketoacidosis.Not obese, no insulin resistance associations (e.g., acanthosis nigricans).Autosomal-dominant family history.Intermittent or continuous insulin dependency.No insulin-resistance co-morbidities (e.g., hypertension, dyslipidaemia).
No differentiating tests.Negative for diabetes-specific autoantibodies.
Gestational diabetes
Only occurs in pregnancy.
No differentiating tests. Detected by screening during pregnancy with an oral glucose tolerance test. [1]

Type I glycogen storage disease

Glycogen storage disease type III (GSD III)
Differentiating features for GSD III include growth retardation. About 70% of patients have muscle weakness, but this is usually not clinically significant in childhood.Hypoglycaemia is common, but is not always present, and is usually less severe than in GSD I. Patients may be able to tolerate longer periods of fasting than those with GSD I.Infants may be asymptomatic with a typical schedule of frequent feedings and do not become as severely ill with infections and other stressors that disrupt feeding as do children with GSD I.
Plasma cholesterol, creatine kinase (CK) concentrations, and urinary ketones should be measured early in childhood to distinguish from GSD I.Elevations in AST and ALT are usually higher (may be >1000 units/L) than in GSD I.Mutation analysis is now the preferred method used to establish a specific diagnosis for this disease.
Glycogen storage disease type VI and IX (GSD VI and IX)
Patients with GSD VI (glycogen phosphorylase deficiency) and GSD IX (phosphorylase kinase deficiency) are often clinically indistinguishable.Hypoglycaemia is not as severe as in GSD I or GSD III, and so symptomatic hypoglycaemia during infancy is uncommon unless there is a prolonged fast, which may be associated with hyperketosis.Metabolic acidosis is rare.Common presenting symptoms are an enlarged liver and distended abdomen noted during a physical examination.Physical growth may be impaired during childhood and onset of puberty is frequently delayed, but catch-up growth results in normal adult height.Clinical and biochemical abnormalities gradually ameliorate, and most adult patients are asymptomatic.
Hypoglycaemia and uric acid levels are usually normal, as is blood lactate (though lactate levels are elevated in patients with a specific mutation in the gamma subunit).Hypercholesterolaemia may occur, and ketosis occurs with fasting.After an overnight fast, blood lactate level is normal and administration of glucagon elicits a brisk glycaemic response without a rise in the blood lactate concentration.A diagnosis of GSD VI or IX can be established by assaying the activity of phosphorylase in purified blood cell fractions: muscle phosphorylase activity, muscle histology, and glycogen content are normal.Mutation analysis is now the preferred method used to establish a specific diagnosis for these diseases.
Glycogen storage disease type XI (GSD XI)
GSD XI (Fanconi-Bickel syndrome) is an extremely rare disorder caused by a deficiency in the facilitative glucose transporter GLUT-2 that has an essential role in the liver, pancreas, intestine, and kidney.Patients usually present in infancy with symptoms of hypoglycaemia as the interval between meals increases.Differentiating signs and symptoms include hypophosphataemic rickets and a Fanconi-like tubulopathy, which are characteristic features.Many patients have short stature and may have chronic diarrhoea from carbohydrate malabsorption.
Fasting ketotic hypoglycaemia and postprandial hyperglycaemia are essential distinguishing features, developing due to impaired hepatic uptake of glucose and disordered insulin secretion.Other laboratory findings include glucosuria, proteinuria, phosphaturia, hypergalactosaemia, generalised aminoaciduria, and elevated alkaline phosphatase.Mutation analysis of the GLUT-2 gene confirms a diagnosis of GSD XI.
Fructose-1-6-bisphosphatase deficiency
Fructose 1-6-bisphosphatase deficiency is an extremely rare gluconeogenesis disorder that shares many clinical and laboratory features with GSD I.Some infants present with recurrent hypoglycaemia and severe lactic acidosis in the first month of life.Hypoglycaemia occurs between feedings, with prolonged fasting or intercurrent illness.Hepatomegaly develops due to fatty infiltration and is not due to glycogen accumulation.
The biochemical abnormalities are similar to those in GSD I, but in contrast to GSD I, when glucagon administration is performed in the fed state it elicits a brisk glycaemic response.Although genetic testing is available, leukocyte analysis or liver biopsy is often required for diagnosis.

Typhoid infection

Malaria
May be recurrent fever pattern.
Blood smear for malaria.
Dengue
May be accompanied by diffuse rash.
Serology for dengue (positive only after 1 week of infection).
Typhus
Exposure to ticks, presence of eschar.
Serology for Rickettsia.
Leptospirosis
Usually after history of exposure to fresh water (swimming, rafting, etc.).
Serology for leptospirosis (positive only after 1 week of infection).
Mononucleosis
Sore throat and lymphadenopathy.
Lymphocytosis in blood count.Positive serology (positive only after 1 week of infection).
Brucellosis
Exposure to unpasteurised milk products.
Positive serology or blood culture.

Ulcerative colitis

Crohn's disease
Signs and symptoms are similar to those of UC so it is difficult to differentiate between these 2 types of inflammatory bowel disease by history and physical examination alone. However, Crohn's disease often has perianal involvement, rectal sparing, and a tendency to form fistulae.
Endoscopy and biopsy. Distinguished from UC by inflammation that extends deep to the muscularis mucosae, the presence of granulomata (in about 35% to 50% of cases), and a relative lack of depletion of goblet cells on histology. Crohn's disease can affect the upper GI tract including the small bowel, so a more extensive GI work-up is often necessary in cases of diagnostic uncertainty.Serology: about 70% of patients with UC have positive perinuclear antineutrophil cytoplasmic antibodies, and approximately 70% of patients with Crohn's disease have positive anti-Saccharomyces cerevisiae antibody. [21]
Indeterminate colitis
In the 10% to 15% of patients with inflammatory bowel disease involving only the colon, Crohn's disease cannot be distinguished from UC and a diagnosis of indeterminate colitis is made.Indeterminate colitis evolves in most patients to a definite diagnosis of UC or Crohn's disease on follow-up.
Endoscopy and biopsy.Serological markers may help.
Radiation colitis
Patients have a history of receiving radiotherapy.
Endoscopy and biopsy; histological findings support this diagnosis.
Infectious colitis
History of recent exposure or travel.Usually self-limiting.
Stool culture/biopsy.
Diverticulitis
Older age, fever, nausea, diarrhoea, or constipation.
Leukocytosis, CT scan. Sigmoidoscopy and barium studies contraindicated in acute diverticulitis due to risk of perforation.
Irritable bowel syndrome
Lower abdominal pain and bloating associated with alteration of bowel habits and abdominal discomfort relieved with defecation.
Patients have an absence of abnormal laboratory test, and normal levels of inflammatory markers. Endoscopy and biopsies are normal.
Mesenteric ischaemia/ischaemic colitis
Older age, history of cardiovascular disease.
CT scan/endoscopy. Typical finding is thickening of the bowel wall in a segmental pattern.Endoscopic findings include pale mucosa with petechial bleeding. Bluish haemorrhagic nodules may be seen representing submucosal bleeding; these correspond to 'thumbprints' seen on radiographic studies.
Vasculitis
Abdominal pain, bloody stool. Systemic symptoms (fever, malaise, weight loss), vasculitis skin rash.
Biopsy shows vasculitis pattern (leukocytoclastic, necrotising).
Prolonged use of cathartics
History of use.
Melanosis coli on endoscopy.

Umbilical hernia

Epigastric hernia
Located in the midline of the upper abdomen, cephalad to the umbilicus, as a result of defects in the linea alba.Defects may be multiple.Unlikely to cause strangulation/obstruction as only pre-peritoneal fat herniates through the defect.
No differentiating tests.
Hernia of the umbilical cord
May occur in a newborn with defects in both the umbilical fascia and peritoneum.Intestines herniate into the substance of the cord itself, covered only by amnion.
No differentiating tests.
Omphalocoele
Results from a defect at the umbilicus, through which abdominal contents herniate.Is covered only by an outer layer of amnion and inner layer of peritoneum.Omphalocoeles are not covered by skin.
No differentiating tests.

Unstable angina

Stable angina
Pain occurs only in context of exertion or emotional stress, not worsening over time, and relieved by nitrates or rest.
ECG may be normal in the absence of pain but may show ST depression during episodes of angina or on stress testing.
Non-ST elevation myocardial infarction
Clinical presentation may be indistinguishable.
ECG may be normal or show ST depression or T wave inversion. Cardiac biomarkers (troponin, CK, CK-MB) are raised.
ST-elevation myocardial infarction
Clinical presentation may be indistinguishable.
ECG shows persistent ST elevation in 2 or more leads. Cardiac biomarkers (troponin, CK, CK-MB) are raised.
Congestive heart failure
Breathlessness, orthopnoea, tachycardia, and peripheral oedema are usually predominant. Chest pain may occur if coronary perfusion is poor.
Echocardiogram shows reduced left ventricular ejection fraction or signs of diastolic dysfunction. CXR may show congestion, cardiomegaly, or pleural effusion.
Chest wall pain
Onset often insidious and may be history of repetitive movement or minor trauma. Pain may be reproduced on palpation or movement. Not improved with rest or nitrates but may be relieved by local injection of lidocaine.
CXR or bone scan may show skeletal pathology such as rib fracture, osteoarthritis, or metastatic tumour. Diagnosis of soft tissue lesions is clinical.
Pericarditis
Recent MI, renal failure, chest irradiation, or associated connective tissue disease.Pain relieved by sitting up and leaning forwards and is worse when lying supine. If pleuropericarditis, the pain may be worse or present only on inspiration.Pericardial rub may be heard.
ECG: concave ST elevation in all leads except aVR; PR segment depression.Echocardiogram may show minimal pericardial effusion, but is frequently normal.
Myocarditis
May be preceded by viral infection.Symptoms of myocarditis include chest pain (which may be pleuritic as a result of concomitant pericarditis), palpitations, fatigue, or signs of heart failure (e.g., peripheral oedema, increasing dyspnoea, and weight gain).
ECG may show evidence of pericarditis or myopericarditis (ST elevation or nonspecific ST-T changes). Other findings include arrhythmias or conduction disturbances.Echocardiogram is helpful in excluding other causes of heart failure (e.g., valvular heart disease).Troponin levels are elevated in up to one third of cases.Serum viral antibody titres may suggest recent viral infection, but testing is rarely indicated in the diagnosis of viral myocarditis or any dilated cardiomyopathy, owing to its low specificity and the delay of rising viral titres, which would have no impact on therapeutic decisions.Anti-myosin scanning helps in diagnosis and when compared with endomyocardial biopsy shows a sensitivity of 83% and a specificity of 53%.MRI shows an area of delayed hyper-enhancement that does not match a coronary artery territory.Endomyocardial biopsy is necessary to establish a confirmed diagnosis of myocarditis. Histological criteria for myocarditis are well established. [43] However, routine biopsy for establishing diagnosis of myocarditis is rarely helpful clinically, since histological diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected.
Aortic dissection
History of hypertension, or Marfan's or Ehlers-Danlos syndrome. Occasionally precipitated by pregnancy.Severe tearing chest pain radiating between shoulder blades.Unequal pulses, inter-arm differential BP, diastolic murmur of aortic regurgitation.
CXR: may show wide mediastinum.CT chest or trans-oesophageal echo: visualisation of luminal flap will confirm the dissection.
Pulmonary embolism
Recent surgery, immobilisation, prolonged air travel, or cancer.Acute shortness of breath, pleuritic chest pain, or syncope.Hypoxia, cyanosis, elevated jugular venous pressure with hypotension, and clear lung fields.
ECG: sinus tachycardia, right bundle branch block, S1Q3T3 pattern.CXR: oligaemic and hyper-lucent lung fields, wedge-shaped infarct if pulmonary infarction.V/Q scan: pulmonary embolism is likely when an area of ventilation is not perfused.
Pleuritis
Recent viral infection or prodrome of infection.Chest pain worse with inspiration.Audible pleuritic rub.
CXR: may show resolving pneumonia.
Pneumothorax
Underlying lung disease, trauma, or recent procedures (such as insertion of central venous line).Acute chest pain with shortness of breath.If large, will lead to tracheal deviation, hyper-resonance, and decreased air entry.
CXR: collapsed lung.
Perforated abdominal viscus
History of previous peptic ulcer disease, diverticulitis, or recent bowel biopsy.Typically presents with abdominal pain. Chest pain is referred but may be mistaken for cardiac origin.Abdominal examination shows localised tenderness and, in cases of peritonitis, generalised tenderness.
Erect CXR and abdominal series: gas under the diaphragm.CT abdomen: confirm the presence of free gas within the abdomen and peritoneal cavity.

Urethritis

Urinary tract infection
Dysuria is common to both urethritis and UTI. However, frequency and urgency characterise UTI, while in urethritis they are typically absent.
Urine culture shows growth of bacteria known to cause UTI.Nucleic acid amplification test (NAAT) is negative for gonorrhoea and Chlamydia.Urine culture in the setting of gonococcal urethritis (GU) and non-gonococcal urethritis (NGU) is typically negative, while tests for gonorrhoea and chlamydial infection may be positive.
Candida balanitis or vaginitis
No differentiating symptoms.
Gram stain, done initially to rule out GU, may show candidal hyphae.KOH prep reveals hyphae.
Non-infectious urethritis
A thorough history usually reveals aetiology: trauma, instrumentation, foreign body insertion, chemical irritation (e.g., spermicides).
Cultures for typical sexually transmitted organisms are negative.
Nephrolithiasis
Intermittent pain with passage of gravel in urine may be present.
Serum electrolytes, urea, and creatinine may show impaired renal function.Both WBCs and RBCs may be present in urine.Microscopic analysis of the urine reveals crystals.
Interstitial cystitis
Pelvic pain, sense of urgency to void, sensation of incomplete bladder emptying, and absence of urethral discharge.
Urine cultures and NAAT are negative.Cystoscopy and biopsy aid diagnosis.
Reactive arthritis (Reiter's syndrome)
An inflammatory arthritis that occurs after exposure to certain gastrointestinal and genitourinary infections. The classic triad of post-infectious arthritis, non-gonoccocal urethritis, and conjunctivitis or uveitis is frequently described but found in only a few cases and not required for diagnosis. [32]Uncomplicated urethritis is not associated with joint symptoms or eye inflammation.
Urine culture and sensitivity testing are negative.ESR or CRP may show non-specific elevation.HLA-B27 may be positive.
Chronic prostatitis
Sensation of pain or pressure. No urethral discharge.
Urinalysis may reveal WBCs.PCR and culture of urine or urethral swab should be performed to rule out Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Ureaplasma urealyticum.A trial of 2 to 4 weeks of antibiotics is recommended. If no response, non-bacterial aetiologies should be sought.

Urinary incontinence in women

Urogenital fistula (urethrovaginal, ureterovaginal, and vesicovaginal fistula)
Continuous urine loss with no association to other symptoms or timing.
After performing thorough pelvic examination - as well as speculum examination for direct visualisation of vaginal pooling and/or fistulous tract - cystoscopy, voiding cystourethrogram, IV pyelogram, or retrograde pyelogram may be performed to evaluate and identify location of suspected urogenital fistula.
Ectopic ureter
Difficult to differentiate clinically.Presentation is variable dependent on location of ureteral orifice.
Total incontinence due to ectopic ureter or urethrocoele may be visualised during physical examination or cystourethroscopy. IV pyelogram can show aberrant anatomy.
UTI
May see haematuria.
Urinalysis may show WBCs, RBCs, nitrites.Urine culture may be positive.
Atropic urethritis/vaginitis
Frequency and irritation with voiding.
Shift in mucosal maturation index from superficial cells to a predominance of parabasal cells.May see increase in vaginal pH.
Pregnancy
Frequency without irritation or incontinence.Low perceived bladder volume.
Urine hCG positive.

Urinary tract infections in children

Appendicitis
Focal right lower quadrant pain, guarding.
CT scan abdomen may show enlarged appendix.
Gastroenteritis
Diarrhoea present.
Rotavirus detection on stool may be positive.
Kawasaki disease
Rash, mucositis, extremity swelling, cervical lymph node swelling, conjunctivitis.No signs may be present in those <6 months of age.
Sterile pyuria, transaminase elevation, coronary ectasia, or aneurysms on echocardiogram (late). [42]
Vulvovaginitis or vaginal foreign body
Hx of sexual activity/abuse, use of bubble baths, bloody vaginal drainage.Vaginal exam shows purulence; palpable foreign body may be present on manual exam.
Group A Streptococcus isolated on vaginal culture.Pinworm prep may be positive.Stool culture may be positive for Shigella flexneri.
Nephrolithiasis
Colicky pain, FHx of urolithiasis, passing of particulate matter in urine.
Urine calcium-creatinine, crystals on microscopic exam.Calculus on abdominal x-ray.
Voiding dysfunction
Urine withholding behaviours (squatting, Vincent curtsy, holding), urgency, frequency, incontinence.
Abnormal urodynamic testing and negative urine cultures.
Sepsis with no urinary tract source
Jaundice, haemodynamic instability.
Positive blood and CSF cultures.
Urethritis
Urethral discharge, pelvic pain.
Urine positive PCR results for gonorrhoea, chlamydia, or candida.
Haemorrhagic (viral) cystitis
Haematuria more likely.
Negative urine culture.
Interstitial cystitis
Specific symptoms of urinary frequency, urgency, bladder pain with relief on voiding.
Negative urine culture, hypervascular bladder mucosa, and linear scarring on cystoscopy. [43]
Glomerulonephritis
Swelling of hands or feet; gross haematuria; hypertension.
Significant proteinuria; red cell casts on urinalysis or urine microscopy.
Meningitis
Photophobia, rash, neck stiffness.
Infants <6 weeks of age may have associated meningitis when Escherichia coli is the UTI pathogen.
Renal cancer
Pain, haematuria, no urinary symptoms.
Ultrasound shows an abdominal mass.This is an extremely rare condition in children. Most renal cancers are Wilms' tumours.
Schistosomiasis
Coinfection of bacterial UTIs with parasites, such as Schistosoma species, significantly contributes to morbidity of the genitourinary tract in rural areas of developing tropical countries, resulting in millions of children being infected. [11]Can cause urinary symptoms, including gross haematuria or dysuria.History of travel to tropical countries, even going several years back, as the child may have been asymptomatic for a prolonged period of time.The prevalence of infection among school-aged children can be as high as 90%, even in urban areas. [44]
Standard urine cultures may result in growth only of Staphylococcus and may be disregarded as contamination with normal skin flora. [45] [46]Circulating cathodic antigen (CCA) urine reagent strip: a rapid ELISA test which detects adult worm gut-associated glycoproteins and eggs with a sensitivity of 88.2% (for glycoproteins) and 95.8% (for eggs). Specificity is 100%. Detects S mansoni and S haematobium. It is used as a diagnostic and monitoring tool to assess the success of treatment. [34]

Urinary tract infections in men

Benign prostatic hypertrophy (BPH)
Symptoms of obstructed urine flow may occur.UTI symptoms are uncommon unless obstruction leads to UTI development.
Elevated prostate specific antigen (PSA) may suggest presence of hyperplasia.An enlarged and firm prostate identified on digital rectal examination helps to confirm the diagnosis.
Prostatitis
Most commonly presents with rectal pain and symptoms of obstructed urine flow.Dysuria and urinary frequency may occur.
A tender and boggy prostate on digital rectal examination suggests prostatitis.
Pyelonephritis
Often a complication of UTI, but can occur without history of UTI.May be indicated by costovertebral angle pain with tenderness on examination.
Presence of WBC casts on urinalysis indicates pyelonephritis.
Urinary tract stones
Urinary tract stones may result in damage of the urinary epithelium and consequently dysuria; however, they also typically cause pain.A past medical history of stone formation can help to identify risk.
Both intravenous urogram and CT scan will identify the presence of a urinary tract stone, but CT scan is more accurate and does not require use of intravenous contrast.
Gonococcal urethritis
New or multiple sexual partners implies risk.Frequency and urgency of urination as well as fever are often absent.The presence of purulent urethral discharge is more suggestive of gonorrhoea than UTI. [1]Occurs more commonly in young men.
A gonococcal DNA intra-urethral probe accurately identifies the presence of gonorrhoea.
Chlamydia urethritis
New or multiple sexual partners implies risk.Frequency and urgency of urination as well as fever are often absent.Occurs more commonly in young men.
Urine culture will be sterile.A chlamydia DNA intra-urethral probe accurately identifies the presence of chlamydia.
Bladder cancer
Patients may present with symptoms resembling UTI but often have haematuria. [1] [8]
Cystoscopy with confirmatory tissue biopsy determines the presence of bladder cancer.
Prostate cancer
Symptoms of obstructed urine flow may occur.UTI symptoms are uncommon unless obstruction leads to UTI development.
Elevated PSA suggests presence of malignancy.Tissue biopsy confirms the diagnosis.
Renal cancer
Patients may present with symptoms resembling UTI but often have haematuria. [1] [8]
CT scan will identify the presence of a renal mass.Pathological analysis, typically at the time of surgical removal, confirms the diagnosis.
Epididymitis
Most often presents with scrotal pain and is not associated with dysuria, urgency, or frequency.Tender, swollen epididymis.
Urinalysis and culture are negative in isolated epididymitis, but UTI may be present additionally.
Reiter's syndrome
Symptoms unrelated to the urinary tract may be present, such as arthralgia, back pain, or ocular symptoms.
Urine culture will be sterile.Blood testing may reveal hypergammaglobulinaemia and a positive HLA-B27 tissue antigen.
Behcet's syndrome
Symptoms unrelated to the urinary tract may be present, such as arthralgia, back pain, ocular symptoms, and oral ulcers.
Urine culture will be sterile.Seems to have relationship to HLA-B5 antigen.A positive pathergy test and the presence of serum immune complexes may aid in diagnosis.

Urinary tract infections in women

Over-active bladder
Urinary urgency and frequency in the absence of a UTI.
Negative urine dipstick, microscopic urinalysis, and urine culture.
Urothelial carcinoma of the bladder or upper urinary tract
Microscopic and/or gross haematuria in the absence of a UTI.
Positive urine cytology. Tumour seen on cystoscopy or upper tract imaging.
Non-infectious urethritis
Dysuria, possibly with irritative voiding symptoms, in the absence of a UTI.
Negative urine dipstick, microscopic urinalysis, and urine culture.
Foreign body in bladder
Recurrent or unresolved UTI.
Foreign body (e.g., stone, stitch from prior pelvic surgery) visualised on imaging or cystoscopy.
Vaginitis due to Candida
Presence of vaginal discharge and/or vaginal irritation.
Negative urine dipstick, microscopic urinalysis, and urine culture; positive vaginal cultures.Direct examination yields budding yeasts and hyphae - the use of potassium hydroxide (KOH) enhances the recovery of these fungal elements; yeasts provoke a large white blood cell response with a negative amine test. Normal vaginal flora will be present.
Vaginitis due to trichomonas
Presence of vaginal discharge and/or vaginal irritation.
Negative urine dipstick, microscopic urinalysis, and urine culture; positive vaginal cultures.Direct examination commonly reveals motile parasite with its flagella whipping back and forth; the infection is associated with large numbers of white cells with a positive amine test and the absence of normal vaginal flora.
Bacterial vaginosis and cervicitis due to Neisseria gonorrhoeae, Chlamydia trachomatis, or herpes simplex
Presence of vaginal discharge and/or vaginal irritation.
Negative urine dipstick, microscopic urinalysis, and urine culture.Positive vaginal cultures; positive DNA probe assay for gonorrhoea and chlamydia.
Interstitial cystitis (painful bladder syndrome)
Pain associated with bladder filling as well as urinary urgency and frequency in the absence of a UTI. The course of the disease is usually marked by flare-ups and remissions. [35]Dyspareunia and supra-pubic discomfort as well as anterior vaginal wall tenderness on examination.
Symptoms with negative urine cultures are characteristic of interstitial cystitis.
Urethral diverticulum
May present with dysuria, dyspareunia, and/or dribbling.On physical examination, a fluctuant urethral mass as well as purulent meatal discharge upon mass compression may be noted.
Characteristic radiographic findings on voiding cystourethrography (peri-urethral fluid collection) or T2-weighted MRI (bright image in peri-urethral area).
Infected Skene gland cyst
May present with urethral pain, discharge, and/or urgency and frequency.
May be visualised on MRI.
Pelvic organ prolapse
May present with pelvic fullness or pressure and/or voiding dysfunction.
Diagnosis is clinical.No evidence of infection in urine studies.
Urethral cancer
May present with voiding symptoms or haematuria.Urethral induration may be noted on physical examination.
A urethral mass can be visualised on cystoscopy and confirmed by pathological diagnosis of biopsy specimen.
Radiation cystitis
Hx of pelvic radiation.May have voiding symptoms and/or haematuria.
Findings on cystoscopy include diffuse erythema, oedema, vascularity, petechiae, and patches of pallor.
Post-cyclophosphamide cystitis
Hx of cyclophosphamide treatment.Irritative voiding symptoms.
Diagnosed by cystoscopy (diffuse erythema, oedema, vascularity, petechiae, patches of pallor) and, possibly, biopsy.
Atypical infections of lower urinary tract (fungal, adenovirus, TB)
May present with recurrent voiding symptoms or sterile pyuria.
Diagnosed by culture of atypical organisms.
Asymptomatic bacteriuria
This is not considered a UTI, but is present in up to 20% of the older female population, and its prevalence is even higher in nursing home patients (25% to 33%). [1]
Bacteria and, occasionally, WBCs in the urine in the absence of urinary symptoms.

Urticaria and angio-oedema

Dermatographism
Dermatographism will appear within minutes of scratching or stroking the patient's skin.Unlike urticaria, it will be limited only to sites of contact.
There are no specific laboratory tests to differentiate the 2 conditions.
Atopic dermatitis
The lesions of atopic dermatitis are normally accompanied by a greater degree of surrounding xerosis and erythema than is seen in urticaria.The rash of atopic dermatitis typically lasts beyond 24 hours, which is unusual in simple urticaria.
There are no specific laboratory tests to differentiate the 2 conditions.
Urticarial vasculitis
Lesions in urticarial vasculitis are typically painful, last longer than 24 hours, and often leave residual markings upon their resolution. These characteristics are all unusual in urticaria.
An elevated ESR or C-reactive protein may help distinguish urticarial vasculitis from urticaria.If there is high suspicion of a vasculitic component, a skin biopsy should be considered.
Urticaria pigmentosa
Lesions are typically small macules or slightly raised papules, as opposed to the large wheals seen with simple urticaria.Can be associated with Darier's sign, which is characterised by urticaria and erythema upon rubbing, scratching or stroking affected skin.
An elevated tryptase may help with the diagnosis of urticaria pigmentosa, which is often a feature of systemic mastocytosis.
Systemic mastocytosis
Patients with systemic mastocytosis often have skin findings consistent with urticaria pigmentosa.Symptoms often include profound fatigue, and can other manifestations depend on the organ symptoms affected. Gastrointestinal complaints are most common.
An elevated tryptase raises the suspicion, but does not confirm the diagnosis. A bone marrow biopsy can confirm the diagnosis.
Carcinoid
Patients typically complain of cutaneous flushing. Diarrhoea and respiratory difficulties are also often reported.
The most useful initial test for carcinoid is to measure 24-hour urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), which is the end product of serotonin metabolism.

Uterine fibroids

Adenomyosis
There are no differentiating signs or symptoms.
Distinguished by uterine biopsy and subsequent histopathological examination.Imaging with pelvic ultrasonography and MRI are also helpful. [52]
Endometrial polyp
There may be no differentiating signs or symptoms.
Sonohysterography typically shows a well-circumscribed isoechoic polypoid mass with stalk contained within the endometrial stripe. [27] View imageT2-weighted MRI images may show decreased signal intensity compared with endometrium. [43]
Endometrial hyperplasia
There are no differentiating signs or symptoms.
Endometrial biopsy, and dilatation and curettage, provide differentiation. [53]
Endometrial carcinoma
Because of the high prevalence of uterine fibroids in the general female population, a substantial number of patients with endometrial carcinoma will present with abnormal vaginal bleeding or discharge in association with uterine fibroids. [29]
Endometrial sampling: an abnormal endometrial biopsy would show either precursor histology for endometrial carcinoma (simple/complex hyperplasia or simple atypical/complex atypical hyperplasia) or frank endometrial carcinoma. [29]Dilatation and curettage: persistence of irregular vaginal bleeding despite a negative endometrial biopsy should be pursued by dilatation and curettage. [31]
Uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma, mixed mesodermal tumour)
Rapid growth of the tumour may be present in uterine sarcomas.
No test can reliably diagnose uterine sarcoma.Serial MRI can identify rapid uterine growth and show characteristics associated with sarcomas such as indistinct borders and invasion into contiguous organs. [43]
Pregnancy
Symptoms of pregnancy (e.g., morning sickness) and missed menstrual period are associated with abdominal expansion over a few weeks.On examination, uterine enlargement due to pregnancy usually presents as soft, regular, globular pelvic-abdominal mass with its height coinciding with expected gestational age calculated from the last menstrual period.
Pelvic ultrasonography visualises the pregnancy sac. [52]The urine or blood beta-hCG pregnancy test is positive. Pregnancy tests usually become positive about 26 to 30 days after the first day of the last menstrual period. Serum beta-hCG test is considered positive if levels are above 5 mIU/mL.
Ovarian cancer
Ovarian cancer is differentiated by rapid tumour growth associated with atypical age for leiomyoma (e.g., post-menopausal women not on hormone replacement therapy), rapid weight loss, or ascites.
Pelvic ultrasonography and MRI are useful first-line investigations. MRI may show characteristic low-signal intensity on T2-weighted images seen with uterine fibroids, may show surrounding tissue invasion, and can more exactly define the origin of pelvic masses (uterine versus adnexal). [54]Surgery and histopathological examination provide differentiation. [52]
Tumours of the GI tract and urinary system, lymphomas, and bone tumours
These serious conditions are differentiated by rapid tumour growth associated with atypical age for leiomyoma (e.g., post-menopausal women not on hormone replacement therapy), surrounding tissue invasion, rapid weight loss, or ascites.
Pelvic ultrasonography and MRI are useful first-line investigations.Surgery and histopathological examination provide differentiation. [52]

Uterine prolapse

Cervical elongation
Physical examination is essential for differentiation.Women with pelvic organ prolapse (POP) demonstrate greater descending of the cervix and the vaginal wall when straining.
Vaginal speculum and bimanual examination are the most reliable tests for differentiating between POP and cervical elongation.
Vaginal cyst
Often asymptomatic. The patient may report a soft lump in the vaginal wall or protrusion of a lump from the vagina. Superficial dyspareunia or difficulty inserting tampons may be experienced.
Diagnosis is usually clinical. However, vaginal ultrasound is useful to identify the content of the cyst and its topographical relation with adjacent anatomical structures.

Uveitis

Intraocular foreign body
A complete history may identify a recent traumatic injury or high-risk activities (metal-metal hammering). Therefore, a painful, red eye is more likely due to a foreign body than uveitis.
Fluorescein staining, in addition to fluorescein angiography, may help identify corneal injury or scarring secondary to foreign body entry. Fluorescein angiography may show the site of entry and vascular damage.
Endophthalmitis
History of surgery or previous infection with purulent discharge may help identify a painful eye sensation due to endophthalmitis.
An ocular culture should identify causative organisms in endophthalmitis.
Posterior segment tumour
Tumour and uveitis signs are often similar and overlap. Differentiation is difficult without testing.
Flow cytometry and cell phenotype show tumour cells and vitrectomy aids in removal of cells for analysis.

Vaginitis

Gonorrhoea
Pelvic or lower abdominal pain and fever may be present if ascending infection.
Neisseria gonorrhoeae grown on chocolate agar culture.
Chlamydia
Many are asymptomatic; intermenstrual bleeding, cervicitis, and abdominal pain may be differentiating.
Chlamydia trachomatis on nucleic acid amplification technique.
Cervicitis
Intermenstrual bleeding; friable cervix on physical examination; genital warts may be present if caused by HPV.
Cervical discharge collected for Gram stain may indicate Neisseria gonorrhoeae or Chlamydia trachomatis. Cervical cytological testing may be positive for HPV.

Varicocele

Paratesticular mass
Usually the testis is normal, and the mass is firm and quite large by the time the patient presents.
Ultrasound will show solid mass along the spermatic cord.
Cord hydrocele
Fluid palpable, not veins along the spermatic cord, separate from the testis. Transilluminates using penlight (varicoceles do not transilluminate).
Ultrasound will show fluid collection alongside spermatic cord.
Inguinal hernia
Typically lies superomedial to the pubic tubercle.The patient may report a dragging sensation in the groin or an intermittent bulge that disappears when lying flat.
Ultrasound will show abnormal ballooning of the anteroposterior diameter of the inguinal canal.
Spermatocele
Cyst attached to the head of the epididymis. Smooth and able to get above it on examination. Often transilluminates.
Ultrasound will show cystic structure on head of epididymis clearly separate from testis.

Varicose veins

Telangiectasias
Also known as spider veins. These are small veins that generally do not cause any symptoms but are mainly a cosmetic concern.
Veins are smaller in size (<1 mm). No evidence of reflux on duplex examination.
Reticular veins
Permanently dilated intradermal veins. May be tortuous. Usually asymptomatic.
Veins range between 1 mm and 3 mm in diameter. No evidence of reflux on duplex examination.

Vascular dementia

Depression
Depression is a risk factor for cognitive decline.Severe depression can sometimes be mistaken for dementia. However, much more commonly depression is seen as a feature in patients with established dementia.
Cognitive tests and depression rating scales identify symptoms of depression.Brain CT and MRI: lack of vascular lesions is supportive.
Alzheimer's disease (AD)
Onset of cognitive symptoms before stroke onset (stroke can convert those with sub-clinical AD), lack of clear interval events, gradual course, and rapid forgetting. In many cases, patients probably have a mixed dementia, a combination of AD and vascular disease.
Cognitive testing, brain MRI, PET scan. Lack of vascular lesions on brain MRI supports mainly AD. PET scan shows parieto-temporal hypometabolism and patchy vascular change.
Mild cognitive impairment (MCI)
State of mild memory decline without loss of social or occupational functioning.
Cognitive screening can identify mild memory complaints. Cognitive impairment not severe enough to meet full DSM-IV-TR criteria for vascular dementia supports the diagnosis of MCI.
Lewy body dementia
Vivid visual hallucinations, autonomic instability, and Parkinson's features (shuffling gait, bradykinesia, and falls) are characteristic.Rapid eye movement sleep disorder may be present.
No reliable or valid differentiating test.Brain pathology demonstrates the presence of round, eosinophilic, intraneuronal inclusions called Lewy bodies. Neuropathological findings include neurofibrillary tangles, amyloid plaques, and Lewy neuritis.
Normal pressure hydrocephalus
Gait disturbance and incontinence may be present as well as dementia.
CT scan and MRI show large non-obstructive dilated ventricles without brain atrophy or vascular lesions.

Ventricular septal defects

Atrial septal defect
The murmur is usually higher up in the left parasternal region and results from flow across the pulmonic valve. Therefore, the murmur is much softer, mid or ejection systolic instead of holosystolic, and the second heart sound may have a wide and fixed (not changing with breathing) split.
An echocardiogram will demonstrate the defect and site of shunting by colour flow.
Patent ductus arteriosus
Associated with a continuous systolic and diastolic murmur at the base of the heart.
An echocardiogram will show the defect at the level of the ductus arteriosus.
Mitral regurgitation
Mitral regurgitation results in a holosystolic murmur most prominent at the mitral area, and may radiate to the axilla or the lower left sternal border depending on the eccentricity of the mitral regurgitation jet.
An echocardiogram will reveal posterior motion of valve leaflets during mid-systole without evidence of a ventricular septal defects (VSDs).
Tricuspid regurgitation
Tricuspid regurgitation results in a holosystolic murmur at the lower left parasternal region. A characteristic finding in tricuspid regurgitation shared with other right-sided murmurs is an increase in the murmur intensity with inspiration (Carvalho's sign).
An echocardiogram will demonstrate regurgitant flow across the tricuspid valve without evidence of a VSD.
Pulmonic stenosis
Ejection systolic murmur at the left upper parasternal border.
An echocardiogram will demonstrate turbulence of colour flow and a gradient across the pulmonic valve without evidence of a VSD.
Tetralogy of Fallot
Typical infant presents in the newborn period with a murmur and cyanosis. The diagnosis may have been made antenatally on fetal echocardiogram. Some infants present at a later age with increasing cyanosis, murmur, or hypercyanotic spells. May be associated with genetic syndromes such as DiGeorge syndrome.Physical examination may reveal significant tachypnoea and cyanosis in severe cases, an increased right ventricular (parasternal) impulse, a single second heart sound, and a harsh systolic ejection murmur heard best at the left sternal border. The intensity of the murmur depends on the degree of pulmonary stenosis and decreases with severe stenosis.
Echocardiogram will show the presence of the 3 other key findings in addition to the VSD (i.e., presence of pulmonic stenosis, overriding aorta, and right ventricular hypertrophy).

VIPoma

Infectious gastroenteritis
Recent travel or exposure.
Microscopic examination of the stool for ova and parasites: may isolate specific ova and/or parasites, including Giardia and Entamoeba histolytica.
Osmotic diarrhoea
Symptoms resolve with fasting.
Contrast-enhanced intestinal radiographs: help differentiate from intestinal hypermotility and inflammatory bowel disease.Biopsy rules out infectious causes as well as inflammatory bowel disease.
Ileal bile acid malabsorption
Lower volume of stool output. Symptoms resolve with fasting.
Cholestyramine trial: binding of excess bile salts reduces the diarrhoea that is typically a symptom of excess bile reaching the colon.
Gastrinoma
Acidic diarrhoea, increased gastric acid production, gastro-oesophageal reflux disease, pain/peptic ulcer disease, absence of metabolic acidosis.
Serum gastrin levels: elevated.
Carcinoid syndrome
Associated severe flushing.
24-hour urinary 5-hydroxyindoleacetic acid: elevated.
Somatostatinoma
Steatorrhoea, diabetes mellitus, gallstones.
Plasma somatostatin levels: elevated.
Crohn's disease
Less severe diarrhoea and associated abdominal pain. Perianal lesions, mouth ulceration, blood in stools.
Plain film abdominal radiograph: small-bowel or colonic dilatation, calcification, sacroiliitis, and/or intra-abdominal abscesses.Colonoscopy: aphthous ulcers, hyperaemia, oedema, cobblestoning, and/or skip lesions.Biopsy: transmural involvement with non-caseating granulomas.
Ulcerative colitis
Less severe diarrhoea and associated abdominal pain. Rectal bleeding, blood in stools, arthritis, spondylitis, skin rash, uveitis, episcleritis.
Plain film abdominal radiograph: ulcerated colon usually contains no solid faeces, dilated loops with air-fluid level secondary to ileus.Colonoscopy and flexible sigmoidoscopy: continuous uniform rectal involvement, loss of vascular marking, diffuse erythema, mucosal granularity, fistulas, and/or mild 'backwash' ileitis in pancolitis.Biopsy: continuous distal disease, mucin depletion, basal plasmacytosis, diffuse mucosal atrophy, absence of granulomata, and anal sparing.
Colon carcinoma
Less severe diarrhoea and improvement with fasting. Rectal bleeding, positive FHx, anaemia.
Colonoscopy: ulcerating exophytic mucosal lesion that may narrow the bowel lumen.Biopsy: characteristic pathological appearances and degree of tumour differentiation.
Laxative abuse
Long-term laxative use. Abates when laxatives withheld.
Clinical diagnosis.
Hyperthyroidism
Less severe diarrhoea. Palpitations, menstrual irregularity, tremor, anxiety, diaphoresis, exophthalmos.
Thyroid function testing: reduced TSH, elevated T3, and elevated T4.
Addison's disease
Systemic collapse, hyperpigmentation, salt craving.
Serum electrolyte levels: reduced serum sodium, reduced serum calcium, elevated potassium.ACTH level: elevated.
Medullary cancer of the thyroid
Neck mass, FHx of type 2 multiple endocrine neoplasia A or B.
Serum calcitonin levels: may be elevated.Biopsy: characteristic pathological appearances.
Phaeochromocytoma
Hypertension, palpitations, diaphoresis.
Urinary or serum catecholamine, metanephrine, normetanephrine levels: elevated.
Neuroblastoma
Rarely occurs over the age of 10.
Serum and/or urinary catecholamines: may be elevated.

Viral gastroenteritis

Bacterial gastroenteritis
High fever, bloody diarrhoea, or severe diarrhoea suggests bacterial infection.
WBC count may be elevated. Stool microscopy and culture are differentiating tests. Stool can show a high WBC count, and culture may grow enteropathogenic bacteria, such as Campylobacter jejuni, Salmonella species, enteropathogenic Escherichia coli, Shigella, Yersinia enterocolitica, Shiga toxin-producing E coli, or Vibrio cholerae.
Protozoal infections
May be suspected if a patient has recently travelled to countries where protozoal infections are endemic (e.g., Mexico, India, South America, many parts of the US). Signs and symptoms vary based on the parasite.Amoebic dysentery presents with bloody diarrhoea with excessive mucus and abdominal pain.Giardiasis can present with bloating and prolonged diarrhoea.Parasitic infections should always be ruled out in immunocompromised patients.
Traditionally, stool microscopy is used to identify Giardia lamblia, Entamoeba histolytica, cryptosporidium, or other parasites. But stool antigen testing or serology can also be used.
Helminthic infections
These infections are common in immunocompromised patients and in immigrants from endemic areas.
Stool microscopy can identify the worm.
Clostridium difficile colitis
Recent antibiotic use is a risk factor.Some cases can progress very rapidly to serious toxic megacolon, so early detection and presumptive treatment with oral metronidazole or vancomycin may be warranted.
WBC count may be elevated. A stool test for C difficile toxin would be positive.
Food poisoning
Usually suspected if multiple people develop symptoms after eating the same contaminated food or drink. Symptoms can vary from nausea, vomiting, abdominal pain, and/or diarrhoea, which start suddenly a few hours to 2 days after eating the contaminated food.
Stool cultures might not be useful as they are of low yield and most of these diseases are caused by toxins. Toxin testing may be available for epidemiological purposes.

Viral gastroenteritis in children

Bacterial gastroenteritis
Often clinically indistinguishable.Features suggestive of a bacterial aetiology include fever >39°C (>102.2°F ), bloody diarrhoea, significant abdominal tenderness, and toxicity.
Presence of faecal leukocytes.Three fresh stool samples should be collected on different days and sent for microscopical examination for culture. A positive stool culture confirms the diagnosis.
Protozoal gastroenteritis
Protozoal parasites such as Giardia intestinalis, Entamoeba histolytica, and Dientamoeba fragilis are uncommon causes of gastroenteritis, but are more likely if diarrhoea lasts >14 days and the child has been to an endemic area.The onset is usually insidious and the course is chronic.There may be multi-system involvement and weight loss.
Presence of ova, cysts, and parasites on stool microscopy. Three fresh stool samples should be collected on different days.
Food poisoning
Food poisoning results from ingestion of food containing preformed toxins produced by bacterial contaminants.Presenting symptoms include profuse vomiting and abdominal cramps. There is often a history of similar illness in those people who ate with the patient. Onset of symptoms within a few hours suggests staphylococcal food poisoning whereas onset between 24 and 48 hours suggests salmonellosis.
Stool specimen positive for culture or presence of specific toxin.
Antibiotic-associated diarrhoea
History of antibiotic use.Approximately 10% to 15% of children who are given antibiotic treatment develop diarrhoea that is often self-limited and dose related.
Clinical diagnosis.
Pseudomembranous colitis
History of antibiotics such as clindamycin, amoxicillin/clavulanate, and second- and third-generation cephalosporins in particular predispose to overgrowth of Clostridium difficile and development of pseudomembranous colitis.Affected patients often present with explosive watery diarrhoea, fever, vomiting, abdominal cramps, and tenesmus.
Stool culture positive for C difficile or enzyme immunoassay (EIA) for its toxins.
Intussusception
Colicky abdominal pain, vomiting, and passage of 'redcurrant-jelly' stool.The pathognomonic sign is an elongated mass in the right upper quadrant or epigastrium with a feeling of emptiness in the right lower quadrant (Dance's sign).
Plain abdominal x-rays may show dilated loop of intestine, air-fluid levels, paucity of air in the right lower quadrant, and a soft mass in the right or mid abdomen.Abdominal ultrasonography may show a tubular mass ('sandwich' or 'pseudokidney' sign) in longitudinal views and a target appearance ('doughnut' sign) in transverse views.
Appendicitis, acute
Usually presents with nausea, vomiting, fever, and right lower quadrant pain at McBurney's point.Pathognomonic signs include localised tenderness and rebound tenderness.Diarrhoea is characteristically absent.
WBC shows leukocytosis and a differential count shows a predominance of polymorphonuclear cells.If doubt exists, the diagnosis can be confirmed by abdominal ultrasound or CT scan, which may show an oedematous, distended, and non-compressible appendix.
Coeliac sprue
The onset of the disease coincides with the introduction of gluten into the diet.Typically presents with diarrhoea, vomiting, irritability, wasting, abdominal distension, and failure to thrive.Stools are characteristically foul smelling, pale, loose, bulky, and frothy.
The antitissue transglutaminase IgA antibody test is highly sensitive and specific.Proximal small bowel biopsy shows villous atrophy.
Cystic fibrosis
There may be a positive family history of cystic fibrosis or history of meconium ileus or meconium plug syndrome in the neonatal period.Clinical features include chronic diarrhoea, recurrent respiratory infections, failure to thrive, abdominal distension, nasal polyps, and digital clubbing.Stools are bulky, greasy, and offensive.
Sweat chloride test shows a chloride content of ≥60 mmol/L (≥60 mEq/L).
Crohn's disease
Chronic intermittent diarrhoea, urgency to defecate, abdominal cramps, rectal bleeding, anorexia, aphthous ulcers, peri-anal fistula, and peri-anal abscess.Extra-intestinal manifestations include failure to thrive, pubertal delay, digital clubbing, intermittent pyrexia, arthritis, erythema nodosum, anaemia, renal stones, gallstones, and episcleritis.The onset is insidious.
Small bowel series may show fistula, sinus tracts, and strictures.Colonoscopy with intubation of the ileum may show inflammatory changes, ulcers, nodularity, and strictures.Biopsy of the involved bowel may show non-caseating granulomas.
Ulcerative colitis
Chronic bloody diarrhoea, tenesmus, urgency, and abdominal pain.The onset is insidious and nocturnal diarrhoea is characteristic.Extra-intestinal manifestations include failure to thrive, pyoderma gangrenosum, sclerosing cholangitis, chronic active hepatitis, and ankylosing spondylitis.
Air-contrast barium enema may show mucosal ulcerations and granularity in the colon and a 'lead pipe colon'.Colonoscopy may show micro-ulcers, erythema, oedema, and friability of the mucosa.Biopsy of the involved bowel shows mucosal inflammation.

Viral meningitis

Encephalitis
Patients with viral meningitis have normal cerebral function. Abnormal cerebral function such as altered behaviour, or speech or motor disorders, particularly when seen in association with fever, suggests a diagnosis of encephalitis.
Encephalitis is a clinical diagnosis. The CSF profile will be similar to that seen in viral meningitis but the aetiological agents are sometimes different.
Meningitis, bacterial
No differentiating symptoms and signs.
Typical CSF in acute bacterial meningitis will show a neutrophilic pleocytosis, elevated CSF protein, and decreased CSF glucose. Bacteria may be seen on Gram stain. An aseptic profile is seen in meningitis due to syphilis, Lyme disease, rickettsia, and brucellosis. However, CSF or blood culture may yield an aetiological agent such as meningococcus.
Drug-induced meningitis
No differentiating symptoms and signs.NSAIDs, trimethoprim/sulfamethoxazole, amoxicillin, ranitidine are culprit drugs.
This is a diagnosis of exclusion. CSF typically shows a neutrophilic pleocytosis. Symptoms resolve once the offending drug is stopped.
Tuberculous meningitis
Presentation is usually more chronic with a prodromal period of general malaise and fever preceding meningitis.
Presents with a lymphocytic pleocytosis.CSF protein is usually markedly elevated; CSF glucose is depressed.Diagnosis rests on positive microscopy or culture.CXR may be abnormal.
Cryptococcal meningitis
Presentation is often insidious with onset of headache and fever over weeks or months. A rash resembling molluscum contagiosum may be present in disseminated cryptococcal disease.
Testing CSF for cryptococcal antigen has a sensitivity of almost 100% for cryptococcal meningitis.In HIV-positive patients the fungal burden is high, leading to high CSF pressures. The CSF leukocyte count may be low. An India ink stain or cryptococcal antigen is usually positive.HIV-negative patients have higher CSF leukocyte counts and the India ink stain is positive in only half of cases.

Vitamin B12 deficiency

Folic acid (vitamin B9) deficiency
Generally does not present with neurological symptoms. Rare in the present era of folic acid fortification in the US.
Serum folate levels are low.Beware that low serum folate can falsely lower vitamin B12 levels.Treat with folic acid and retest.
Myelodysplastic syndrome (MDS)
Presents with macrocytic anaemia and is difficult to differentiate from vitamin B12 deficiency initially.MDS is a group of disorders characterised by a clonal chromosomal abnormality, ineffective and dysplastic haematopoiesis resulting in ≥1 cytopenias, and a varying predilection to develop acute myeloid leukaemia.These disorders either can arise primarily without any precipitating event or may be related to previous treatment with either chemotherapy or radiation.
FBC in MDS shows normochromic or macrocytic red cells; about 40% of patients have neutropenia, and >30% have thrombocytopenia. Morphological abnormalities are found such as oval macrocytic red cells and granulocytes with the pseudo-Pelger-Huet anomaly (hypogranular and hypolobulated granulocytes).Bone marrow histopathology in MDS demonstrates dysplasia in a proportion of undifferentiated myeloblasts.Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts (abnormal erythroid precursor cells that have granules around the nucleus).
Alcoholic liver disease
May present with macrocytic anaemia and nutritional deficiencies. History should reveal alcohol use.
Elevated liver enzymes.Liver biopsy histopathology shows fatty change, inflammation, and variable amounts of fibrosis leading to cirrhosis in severe, chronic alcoholic liver disease.
Hypothyroidism
May present with macrocytic anaemia.May show signs of muscle and joint pain, weakness in the extremities, and fatigue; delayed relaxation of deep tendon reflexes strongly suggests hypothyroidism.
Elevated TSH, decreased T3 and T4, and elevated CK.
Peripheral neuropathy
Compression neuropathies and neuropathies due to diabetes or thyroid disease may be difficult to differentiate from neurological symptoms of vitamin B12 deficiency.
Nerve conduction studies and EMG are helpful in confirming neuropathy and characterising the neuropathy; that is, demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy.Treatment with vitamin B12 may improve symptoms, but neuropathy may also be irreversible.
Diabetic neuropathy
Paraesthesia is a common feature and may occur in the extremities as a result of neuropathy in those with prolonged undiagnosed diabetes. Other types of neuropathy may be present in diabetes, including autonomic neuropathy.
Antiglutamic acid decarboxylase antibodies, islet cell antibodies, and insulin auto-antibodies are present in 85% of patients with type 1 diabetes at the time of diagnosis, but may disappear within a few years.
Drug-induced macrocytosis
Macrocytosis due to certain medicines, including hydroxyurea, methotrexate, zidovudine, azathioprine, capecitabine, and cladribine.
Usually a clinical diagnosis. Serum drug levels may confirm the association.
Dementia
Characterised by cognitive (memory) changes, psychiatric symptoms, personality changes, problem behaviours, and changes in day-to-day functioning.May be due to multiple different factors that are clinically indistinguishable from vitamin B12 deficiency.
A mental state examination or neuropsychiatric testing should be conducted if the diagnosis is uncertain.Vitamin B12 testing is normal.
Depression
Characterised by persistent low mood causing varying levels of social, cognitive, occupational, and physical dysfunction.Depression is diagnosed clinically with a finding of >5 of the following symptoms, present during the same 2-week period: depressed mood, anhedonia, weight changes, libido changes, sleep disturbance, psychomotor problems, low energy, excessive guilt, poor concentration, and suicidal ideation.
Vitamin B12 testing is normal.
Pernicious anaemia (PA)
Patients present with symptoms of anaemia and vitamin B12 deficiency. They may also have fever and complain of gastric pain or discomfort. Common features include tiredness, dyspnoea, paraesthesia, sore red tongue, diarrhoea, and mild jaundice.
Once vitamin B12 deficiency is confirmed, antiparietal cell (APC) antibody can determine whether PA is the cause.Highly sensitive (85%), but not specific. Can be elevated in atrophic gastritis.Once patient is given intrinsic factor, and vitamin B12 level is normal, gastrin levels will normalise.
Crohn's disease
Crohn's disease can affect any part of the GI tract, and symptoms may be extremely variable.
The classic findings on histological examination include involvement of all layers of the bowel wall by granulomas, ulcerations, and acute and chronic inflammation.
Coeliac disease
Patients present with unexplained GI symptoms, chronic diarrhoea, unexplained iron-deficiency anaemia, vitamin D deficiency, or a skin rash consistent with dermatitis herpetiformis.Other situations include failure to thrive, short stature, recurrent severe aphthous stomatitis, recurrent spontaneous abortion, and infertility.
Immunoglobulin A antigliadin and anti-endomysial antibodies.Small-bowel histology is the most specific and sensitive test, showing villous atrophy and mucosal inflammation with hyperplastic changes to crypts.Iron-deficiency anaemia is the most common clinical presentation in adults.Folate (and less commonly vitamin B12) deficiency may lead to macrocytic anaemia.
Peptic ulcer disease from Helicobacter pylori infection
H pylori is a gram-negative, micro-aerophile bacterium that inhabits the stomach and duodenum. It causes a chronic low-level atrophic gastritis and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer.Over 80% of people infected with the bacterium are asymptomatic.
The carbon urea breath test is positive.The most reliable method for detecting H pylori infection is endoscopic biopsy. Histopathology shows gastric atrophy, inflammation, and bacterial organisms on special stains.
Chronic pancreatitis
History of gallstone disease or alcohol misuse.Characterised by recurrent or persistent abdominal pain and progressive injury to the pancreas and surrounding structures, resulting in scarring and loss of function.
Ultrasound or CT imaging of the abdomen may reveal fibrosis and calcification of the pancreas.Evaluation of pancreatic enzymes is the most sensitive and specific test for diagnosing mild-to-moderate pancreatic insufficiency or chronic pancreatitis, but it is available in only a few centres. Pancreatic juice is collected with a gastroduodenal tube during exogenous hormone stimulation with cholecystokinin and/or secretin.Helps differentiate pancreatic from non-pancreatic types of malabsorption.
Small-intestinal bacterial overgrowth
History may show conditions that alter intestinal anatomy, motility, and gastric acid secretion. These include use of proton-pump inhibitors and anatomical disturbances in the bowel, including fistulae, diverticula, and blind loops created after surgery.
The definitive investigation requires culture of jejunal fluid that grows >10^5 bacteria/mL.Hydrogen breath testing may show malabsorption but is not very sensitive or specific for bacterial overgrowth.A trial of treatment with antibiotics for 1 week may give the diagnosis.
Zollinger-Ellison syndrome
A condition caused by a gastrin-secreting tumour that causes hypersecretion of gastric acid leading to ulcer disease. It most commonly presents with abdominal pain, diarrhoea, and gastro-oesophageal reflux. Less common presentations include weight loss, GI bleeding, nausea, and vomiting.
Elevated level of fasting serum gastrin in the absence of achlorhydria, and either a positive secretion test or histologically demonstrated neuroendocrine tumour.
Tropical sprue
Believed to be initiated or sustained by a still-undefined infection.Presents with symptoms and signs of malabsorption, stomach pain, diarrhoea, and bloating.The relapse rate is substantial in treated patients who remain in, or return to, endemic areas in the tropics.
Endoscopy and small bowel biopsy: progressive villus atrophy in the small intestine similar to coeliac disease.Therapeutic trial with tetracyclines for 6 months normalises mucosal structure in the small intestine.
Fish tapeworm (Diphyllobothrium latum)
Fish tapeworm is native to Scandinavia, western Russia, and the Baltic states, though it is now also present in North America, especially the Pacific North-west.Infection arises following eating raw fish or fish products.Patients present with symptoms of malnutrition including anaemia.
Tapeworm eggs appear in the faeces 5 to 6 weeks after infection, and faecal examination may confirm the diagnosis.
HIV infection
Malnutrition is common in HIV disease, particularly in resource-poor areas. A cycle of opportunistic infection causing loss of weight and poor appetite, together with diarrhoea and malabsorption, contributes to this malnutrition.
ELISA testing should be ordered when HIV testing is indicated. False-negatives may occur during the window period immediately after infection and before antibodies to HIV have developed. A positive result should be confirmed with a Western blot or second ELISA. The window period can be reduced to 2 to 4 weeks by using fourth-generation tests and those that include IgM antibodies to HIV.
Alpha-thalassaemia
An inherited autosomal-recessive blood disease.Vitamin B12 requirement is increased in alpha-thalassaemia and, in these patients, vitamin B12 deficiency may be the presenting feature. Patients present with anaemia, hepatosplenomegaly, leg ulcers, and bone pain. This disease is more common in Mediterranean countries, Asia, the Middle East, and South America.
FBC and peripheral smear show microcytosis, erythrocytosis, hypochromia, and mild anaemia.The diagnosis is made by a combination of family studies and the ruling out of both iron-deficiency anaemia and beta-thalassaemia trait.Haemoglobin electrophoresis shows increased ratios of beta- to alpha-globin chains.
Multiple sclerosis
Neurological manifestations of vitamin B12 deficiency can mimic clinical symptoms of multiple sclerosis. However, in almost all cases of multiple sclerosis there are also brain lesions.Variable presentation: multiple episodes separated by space (i.e., neurological symptoms result from lesions in different CNS sites) and time. Symptoms include progressive limb weakness, gait difficulty, ataxia, loss of balance, and paroxysmal vertigo.
Brain MRI typically shows areas of demyelination.CSF examination shows raised IgG and oligoclonal banding.
Syphilis (tabes dorsalis)
History of syphilis infection or sexually transmitted infection.Neurological symptoms of tabes dorsalis and sub-acute combined spinal degeneration may be similar.
The VDRL reaction alone cannot always be depended on in differential diagnosis, as false-positive reactions are not uncommon in lepromatous leprosy, in which case PCR test may be more sensitive and specific.CSF examination is required to diagnose neurosyphilis.CSF VDRL reactivity test is specific but not sensitive for neurosyphilis.CSF fluorescent treponemal antibody absorption (FTA-ABS) reactivity test is sensitive, but not specific for neurosyphilis.

Vitamin B1 deficiency

Peripheral neuropathy
It is not possible to differentiate vitamin B1 deficiency-related neuropathy from other causes of distal peripheral neuropathy such as diabetes, alcoholism (direct toxic effect), vitamin B12 deficiency, malignant disease, and chronic renal failure on clinical grounds.The presence of risk factors may lead to a clinical suspicion of vitamin B1 deficiency.
Electromyography and nerve conduction studies: reveal specific type of peripheral neuropathy.
Acute encephalitis
It is not possible to differentiate Wernicke's encephalopathy from other causes of acute encephalitis such as Miller-Fisher syndrome, multiple sclerosis, variant Creutzfeldt-Jakob disease, paraneoplastic encephalitis, and ventriculo-encephalitis on clinical grounds.The presence of risk factors may lead to a clinical suspicion of vitamin B1 deficiency.
MRI: may show nerve root enhancement in Miller-Fisher syndrome, and active lesions reflecting perivascular inflammation and breakdown of the blood-brain barrier in multiple sclerosis. In paraneoplastic encephalitis, MRI may be unremarkable although T2-weighted hyperintensity may be noted in the mesial temporal lobes and associated limbic structures. Viral encephalitis may show increased T2 signal intensity in the mesial temporal lobes and inferior frontal grey matter.CSF examination for bacterial culture and viral PCR: reveals specific pathogen in infectious encephalitis. CSF protein: raised in most forms of encephalitis. Its presence or absence does not help to differentiate Wernicke's encephalopathy.Anti-GQ1b antibodies: may be positive in Miller-Fisher syndrome.Autoantibodies to glutamic acid decarboxylase: may be present in paraneoplastic encephalitis.
Graves' disease
Graves' disease can cause high-output cardiac failure. Symptoms include weight loss, heat intolerance, and palpitations. Signs include a neck goitre, exophthalmos, lid retraction, and tremor.
Thyroid function tests: high free T4/T3 and suppressed TSH.
Anaemia
Severe anaemia can cause high-output cardiac failure. History of blood loss (e.g., GI, menorrhagia). Examination reveals pallor.
FBC: low Hb and reduced mean cell volume in microcytic anaemia.
Paget's disease
Paget's disease can cause high-output cardiac failure. Symptoms include bone pain, headaches, and hearing loss.
Alkaline phosphatase (bone isoform): elevated isotope bone scan: shows preferential uptake of the isotope technetium in the Pagetic foci.

Vitamin B3 deficiency

Dermatitis
Causes include atopic dermatitis, contact dermatitis, seborrhoeic dermatitis, drug eruptions, Hartnup's disease, lupus erythematosus, porphyria cutanea tarda, and pemphigus.The dermatitis of pellagra is a symmetrical, bilateral and well-defined erythematous rash on exposed areas of skin sensitive to sunlight, similar in appearance to sunburn. [8]
Allergy/patch testing: may reveal reactivity to allergens in atopic and contact dermatitis.Serum IgE levels: elevated in atopic dermatitis.Neutral aminoaciduria: >5 times the upper limit of normal range in Hartnup's disease.Antinuclear antibodies: positive in lupus erythematosus, but not specific for the condition.Anti-double-stranded DNA and anti-Smith antibodies: may be positive in lupus erythematosus, and highly specific for the condition.Plasma and urinary total porphyrins: elevated in porphyria cutanea tarda.Skin biopsy: characteristic changes in the epidermal, dermal, and basal cells present in pemphigus.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Diarrhoea
Characterised by the frequent evacuation of liquid stool, accompanied by an excess loss of fluid and electrolytes, especially sodium and potassium. Diarrhoea can be osmotic, secretory, exudative, malabsorptive, or medication-induced.Absence of dermatitic cutaneous lesions.
Stool examination: may be positive for parasites, infection, or malabsorption.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Dementia
Loss of memory and other intellectual functions due to chronic progressive degenerative disease of the brain such as Alzheimer's dementia.Absence of dermatitic cutaneous lesions.
Neuropsychiatric testing (including mental-state examination): may show evidence of dementia.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Riboflavin (vitamin B2) deficiency
Diet deficient in vitamin B2 causes similar symptoms to vitamin B3 deficiency. Clinical features include sore, burning lips and tongue; cheilosis and angular stomatitis; glossitis and magenta/purple tongue; seborrhoeic dermatitis of nasolabial folds, scrotum, and vulva; photophobia; and anaemia.
Percentage of flavin adenine dinucleotide needed to activate RBC enzyme glutathionine reductase: percentage stimulation index >40% indicates riboflavin deficiency.Riboflavin coefficient: elevated.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Pyridoxine (vitamin B6) deficiency
Diet deficient in vitamin B6, consumption of Kombucha tea, or history of a medication known to interfere with vitamin B6 metabolism such as isoniazid or 5-fluorouracil.Causes similar symptoms to vitamin B3 deficiency. Clinical features include weakness, cheilosis, glossitis, stomatitis, and peripheral neuropathy.
Serum pyridoxal-5-phosphate: low.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Peripheral neuropathy
Nutritional polyneuropathies: for example, vitamin B12 deficiency.Neuropathic signs of pellagra are difficult to distinguish from other types of polyneuropathy.
Serum cyanocobalamin: low in vitamin B12 deficiency.FBC: macrocytic anaemia in vitamin B12 deficiency.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.
Depression
Diagnosed clinically if >5 symptoms, including anhedonia, changes in libido, weight changes, sleep disturbance, low energy, depressed mood, excessive guilt, suicidal tendencies, and poor concentration, are present over a 2-week period.Absence of dermatitic cutaneous lesions.
Clinical diagnosis with no differentiating tests.Urinary metabolites of niacin (N-methyl-nicotinamide and 40% to 60% as N-methyl-2-pyridone-5-carboxamide): normal levels.

Vitamin C deficiency

Systemic vasculitis
Vasculitis may present similarly including presence of constitutional symptoms but also with low-grade fever.
Examination of inflammatory blood markers (ESR, C-reactive protein, and others) might suggest an inflammatory disorder such as vasculitis, as opposed to scurvy, in which inflammatory markers should be normal in the absence of concomitant infection. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Haematological malignancy
Dermatological findings about the lower legs and ankles are less likely.
Examination of FBC or peripheral blood smear should be normal in scurvy but might suggest leukaemia/lymphoma in the appropriate context. Bone marrow biopsy would be further supportive evidence. Radionuclide bone scan should be unremarkable despite possible abnormal MRI findings. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Meningococcaemia
Associated with fever or meningismus.
FBC may be consistent with infection in this condition but should only reveal anaemia in patients with scurvy.Cultures of blood or cerebrospinal fluid may yield meningococcus. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Gonococcaemia
Associated with fever or meningismus.
FBC may be consistent with infection in this condition but should only reveal anaemia in patients with scurvy.Blood cultures may yield gonococcus. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Rocky Mountain spotted fever
Associated with fever or meningismus.
Specific tests for Rocky Mountain spotted fever are unreliable early in the disease. An indirect fluorescent antibody test completed after the first 5 days of symptoms is diagnostic. Before treatment, a skin biopsy can establish a diagnosis as well. A rickettsial blood culture is only available in research centres but is highly accurate. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Ecthyma gangrenosum
Associated with fever or meningismus.
FBC may be consistent with infection in this condition but should only reveal anaemia in patients with scurvy. If systemic symptoms are present, a blood culture for pseudomonas should be completed. Also, a Gram stain and culture on soft tissue or drainage to identify pseudomonas or other water bacteria is warranted. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Child abuse or other blunt trauma
There are no differentiating signs and symptoms.
Radiographic findings may aid in diagnosis as abuse cases often show fractures at varying stages of healing. On x-ray, scurvy shows irregularities and microfractures at the metaphysis and growth plate of the knee and wrist. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Disseminated intravascular coagulation
Associated with fever or severe hypotension. However, these may be symptoms of scurvy with concomitant infection.
FBC may be consistent with infection in this condition but should only reveal anaemia in scurvy. In early DIC, PT and PTT may be prolonged, platelet count low, with elevated D-dimer and plasma degradation products, and reduced plasma factors V and VIII. Later in disease, PT, PTT, and plasma factors normalise, with consistently high D-dimer and plasma degradation products. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Idiopathic thrombotic purpura
There are no differentiating signs and symptoms.
Scurvy is associated with normal platelet count. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Thrombotic thrombocytopenic purpura
There are no differentiating signs and symptoms.
Scurvy is associated with normal platelet count. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Aspirin overdose
History should differentiate.
The plasma salicylate concentration of 724 to 2172 micromol/L (10 to 30 mg/dL or 100 to 300 microgram/mL) determines aspirin usage and a level above 2896 micromol/L (above 40 mg/dL or 400 microgram/mL) indicates toxicity. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Cryoglobulinaemia
Cryoglobulinaemia often displays erythematous macules or purpuric papules of the lower extremities and bloody crusts and ulcers. Raynaud's phenomenon may be present as well.
Laboratory demonstration of serum cryoglobulins indicates cryoglobulinaemia. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Waldenstrom's macroglobulinaemia
There are no differentiating signs and symptoms.
A bone marrow smear shows a specific pattern (10% or greater WBCs with plasma cell differentiation with intertrabecular pattern) in Waldenstrom's macroglobulinaemia. Serum IgM level is high as well. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Autoerythrocyte sensitisation
Autoerythrocyte sensitisation is associated with extreme emotional stress.
Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Ehlers-Danlos syndrome
Diagnosis suggested by joint laxity.
Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Osteogenesis imperfecta
Blue sclera and propensity for fractures.
Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Pseudoxanthoma elasticum
There are no differentiating signs and symptoms.
Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Systemic amyloidoses
There are no differentiating signs and symptoms.
Diagnosis is established by biopsy of an affected organ; microscopy with polarised light reveals green birefringence with Congo red staining; other microscopical techniques may yield similar results. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Henoch-Schonlein purpura
Pruritus.
Anaemia is rare in Henoch-Schonlein purpura. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Goodpasture's syndrome
There may be pulmonary and renal involvement.
Elevated anti-neutrophil cytoplasmic antibodies are not found in scurvy. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Polyarteritis nodosa
MI and ulcers may be seen.
Elevated anti-neutrophil cytoplasmic antibodies are not found in scurvy. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Menkes' disease
Features include white hair colour, early retardation in growth, developmental delay, seizures, and focal cerebral and cerebellar degeneration. Perhaps the only genetic syndrome to be mistaken for scurvy.
Menkes' heterozygotic carriers may have similar changes in long bone metaphyses. [32] Low serum copper (<11micromol/L; <70 mg/dL) and serum ceruloplasmin (<200 mg/L) are found in Menkes'. On microscopical examination of hair, a specific finding of pili torti is found in Menkes' as well. Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.
Acquired limp or limb pain in a child
There are no differentiating signs and symptoms.
Normal serum, leukocyte, and whole blood ascorbic acid levels help rule out scurvy.

Vitamin D deficiency

Primary hyperparathyroidism
There may be a FHx of hyperparathyroidism. Most patients are asymptomatic. However, symptoms include fatigue, poor sleep, anxiety, depression, memory loss, bone pain, and constipation.Although rare, physical examination of the neck may identify a hard, dense, firm mass suggestive of parathyroid carcinoma. [65] An eye examination may demonstrate signs such as band keratopathy (a deposition of calcium just inside the iris).
Elevated serum calcium, elevated intact PTH, and a low-normal or low fasting serum phosphate level.
Multiple myeloma
Symptoms and signs are non-specific and commonly include bone pain and anaemia. Weight loss can also occur.
Elevated serum calcium, low level of intact PTH and 1,25-dihydroxyvitamin D.Bone x-ray shows lytic bone lesions, characteristic of multiple myeloma.Gamma globulin assessment defines the disorder as well.Serum creatinine and urea levels are abnormal in 50% of multiple myeloma patients.Serum and urine protein electrophoresis is diagnostic of multiple myeloma.
Fibromyalgia
A chronic pain syndrome diagnosed by the presence of widespread body pain (front and back, right and left, both sides of the diaphragm) for at least 3 months, in addition to tenderness (digital palpation at an approximate force of 4 kg) of at least 11 out of 18 designated tender point sites as defined by the American College of Rheumatology 1990 classification criteria. [66]
Clinical diagnosis.Normal serum 25-hydroxyvitamin D.
Chronic fatigue syndrome
Characterised by persistent fatigue and other associated symptoms (e.g., musculoskeletal pain, sleep disruption, memory impairments) lasting for 6 months or longer. The fatigue is not related to other medical conditions, disease processes, or identifiable biological causes. Sleep, rest, and activity restriction do not improve symptoms.Patients may present with a low-grade fever, tender lymph nodes, muscle pain/joint stiffness on palpation, tachycardia, hyperventilation, and/or orthostatic hypotension.
Clinical diagnosis.Normal serum 25-hydroxyvitamin D.
Paget's disease
Usually asymptomatic, but may present with severe pain in long bones and, although unusual, in some facial areas.
Normal serum calcium and a markedly elevated serum alkaline phosphatase (due to increased bone remodelling in the Pagetic bone).On x-ray there is a mottled appearance and gross deformities of bone may be seen, such as enlargement of the skull and bowing of the femur or tibia.
Hypophosphatasia
An autosomal-recessive disorder that radiographically resembles rickets.It is an inborn error of metabolism in which activity of tissue-nonspecific (liver/bone/kidney) alkaline phosphatase is deficient. [61]
Defined by low serum alkaline phosphatase activity.Large quantities of phosphoethanolamine are found in the urine.
Metaphyseal dysostoses
Includes Jansen's and Schmid's types of metaphyseal dysostosis and Pyle's disease.Bowing of the legs, short stature, and a waddling gait. [61]
Absence of abnormalities of low serum levels of calcium and phosphate, alkaline phosphatase activity, or vitamin D metabolites.
Blount's syndrome
Condition that causes osteochondrosis of the tibia, resulting in bowing of the legs. May be related to obesity.
Absence of abnormalities of low serum levels of calcium and phosphate, alkaline phosphatase activity, or vitamin D metabolites.

Vitiligo

Piebaldism
Present at birth, non-progressive small lentiginous pigmentations within leukodermas.
Clinical diagnosis.
Waardenburg's syndrome
Achromic patches present at birth, white forelock, heterochromia iridium, dystopia canthorum, deafness and other neurological symptoms, mental retardation.
Clinical diagnosis.
Tuberous sclerosis
Typical ash-leaf-shaped hypopigmented macules, seizures, angiofibromas, and mental retardation.Occurs predominately on the thorax and legs.
Hypomelanotic macules (ash leaf spots) are accentuated with Wood's lamp (UV light).
Hypomelanosis of Ito
Mosaic distribution of hypomelanotic macules and bands of speckled or mottled, greyish-brown to blue-black patches involving the skin, conjunctiva, sclera, tympanic membrane, and oral and nasal mucosa of the affected dermatomes.Hypochromic lesions in distinctive patterns (e.g., whirls, patches, streaks) on trunk, arms, legs, and face.
Clinical diagnosis.
Incontinentia pigmenti
Distribution along Blaschko's lines, history of vesicular eruption perinatally, female gender.
Genetic testing for NF-kappa-B essential modulator (NEMO) mutation.
Atopic dermatitis
History of atopic trait in family, typical distribution pattern, severe pruritus.Inflammatory skin disease and associated pruritus, infiltration, scaling, crusting.
Wood's lamp findings of hypopigmentation, elevated total IgE level, skin biopsy findings of a dendritic epidermal cell population (Langerhans cells and mast cells), which carry IgE receptors and specific IgE.
Pityriasis alba
Asymptomatic ill-defined small patches with fine scaling in children and adolescents, often with atopic trait.
Clinical diagnosis.
Seborrhoeic dermatitis
Distribution pattern to seborrhoeic areas (e.g., scalp, forehead, eyebrow, nasolabial fold, periauricular, central chest, and back), greasy scales, dandruff.
Clinical diagnosis.
Discoid lupus erythematosus
Hyperpigmented, infiltrated rim around leukoderma, follicular plugging, scarring alopecia.
Lesional biopsy positive for direct immunofluorescence (e.g., basement membrane).Hyperkeratosis with perivascular and periappendageal lymphocytic infiltrate in the dermis.
Psoriasis
Hypopigmentation may have annular appearance.
When the plaques are scraped pinpoint bleeding from the skin below is visible (Auspitz's sign). Skin from a biopsy will show clubbed Rete pegs.
Pityriasis versicolour
Polycyclic, well-demarcated, typical upper trunk and shoulder distribution.
Pityrosporum orbiculare fluoresces yellow-green when exposed to Wood's lamp examination.A scrape of skin scales reveals the organism on KOH wet mount.
Leishmaniasis
Residence in or travel to endemic area, history of mucocutaneous granulomas.Ulcers can be moist and exude pus, or dry with a crusted scab.
Skin biopsy shows findings ranging from well-formed granulomas containing numerous lymphocytes and few identified amastigotes to an abundance of parasite-containing tissue macrophages and few lymphocytes.
Melasma
Splotchy areas of hyperpigmented macules on the face. With extensive facial vitiligo the remaining unaffected skin may be mistaken for melasma.
Two main histological patterns: epidermal and dermal. Both patterns have increased numbers of melanocytes. Patients with the epidermal type will have pigmentary accentuation under a Wood's lamp; those with dermal melasma will exhibit no enhancement.
Syphilis
History of sexual contact, lymphadenopathy, other specific skin or mucous membrane lesions.
Positive serology, darkfield microscopy demonstrates Treponema pallidum, delicate, corkscrew-shaped organisms with rigid, tightly wound spirals that move through a forward and backward motion.
Pinta
Widespread pigmentary change with a mixture of hyperpigmentation and depigmentation that can be disfiguring.
Positive serology, T pallidum carateum can be seen on darkfield microscopy of samples taken from the early papules.
Leprosy
Distribution, hypoaesthesia, thickening of nerves, extended residence in or migration from endemic area.
Tests for diagnosis include viral culture, serology, pp65 antigenaemia test, histopathology and nucleic acid amplification, and detection systems, most commonly PCR.
Chemically induced leukoderma
Starts at sites of exposure to melanotoxic agents. [13] May progress to be clinically indistinguishable from vitiligo.
Clinical diagnosis.
Melanoma-associated leukoderma
May be indistinguishable from vitiligo; history of melanoma, leukoderma at an excision site, or melanoma or metastases found upon examination.
Biopsy of suspicious melanocytic lesions characterised by loss of pigmentation in the primary lesion and an eccentrically placed hypopigmented macule.
Frostbite
Well-defined leukoderma in areas of previous traumatic cold exposure.
Clinical diagnosis.
Hypopigmented cutaneous T-cell lymphoma
Less well-circumscribed than vitiligo, mixed hypo- and depigmentation.
Immunophenotype CD4 is positive, and CD7 negative; CD25 positivity is variable.
Hydroquinone-induced dermatopathy
Ill-defined or patchy areas of hypopigmentation, history of using bleaching creams.
Clinical diagnosis.
Corticosteroid-induced dermatopathy
Ill-defined hypopigmentation, localised to area of topical or local corticosteroid therapy; associated dermal and epidermal atrophy, telangiectasia, purpura, acne.
Clinical diagnosis.
Melanocyte receptor antagonist-induced dermatopathy
Therapeutic agents (specifically with Imatinib mesilate and SU11428) targeting C-kit (receptor molecule in a signalling pathway essential for melanocyte development and survival) may trigger or worsen vitiligo, may also induce hypopigmentation of skin or hair.
Clinical diagnosis.
Vogt-Koyanagi-Harada syndrome
Acquired leukoderma associated with ocular and auditory compromise.
Clinical diagnosis.
Idiopathic guttate hypomelanosis
Small, often circular hypopigmented macules preferring lower extremities, slowly progressive accumulation of isolated lesions.
Wood's lamp findings of hypopigmentation and skin biopsy with epidermal atrophy, patchy decrease or absence of melanocytes and melanin, flat Rete ridges, and basket weave hyperkeratosis.
Progressive macular hypomelanosis
Progressive hypopigmented patches on back and abdomen of young patients.
Skin biopsy with diminished pigment in the epidermis and a normal-looking dermis. Electron microscopy shows a shift from large melanosomes in normal-looking skin to small aggregated, membrane-bound melanosomes in hypopigmented skin.

Volume depletion in adults

Dehydration
Implies a loss of pure water, leading to hypertonicity and hypernatraemia.The term is often misused to imply volume depletion.However, volume depletion means both a salt and a water loss, leading to decreased intravascular volume.Symptoms include fatigue, lethargy, dizziness, and increased thirst.
Blood chemistry: hypernatraemia supports a diagnosis of dehydration.Serum osmolality: elevated in dehydration. The hypertonicity exists due to an increased sodium concentration.
Heart failure
Symptoms include exertional dyspnoea, orthopnea, paroxysmal nocturnal dyspnoea, and peripheral oedema.Signs of volume overload such as pleural effusions, rales, distended neck veins, gallop rhythm, and peripheral oedema may be present in heart failure, which would not normally be present in volume-depleted patients.Volume repletion may actually make heart failure worse if expansion leads to pulmonary oedema. When heart failure is accompanied by volume depletion from over-diuresis, only small amounts of volume resuscitation are necessary for management, in contrast to volume depletion without heart failure, when large volumes of fluid are appropriate.
Echocardiogram: demonstrates a low ejection fraction.
Hepatorenal syndrome
Volume depletion occurs as a result of shunting of blood to the splanchnic circulation. May have symptoms or signs of chronic hepatic disease (e.g., jaundice, spiders, ascites).
Evidence of liver dysfunction; urine Na usually <10 mmols/L (mEq/L).
Cardiogenic shock
May occur after an acute coronary syndrome, and potential findings include chest pain, dyspnoea, diaphoresis, nausea, or dusky extremities.
Echocardiogram: demonstrates a low ejection fraction and possible structural damage or malfunction.Biochemical cardiac markers: reveal elevated troponins and CK-MB.
Sepsis
Patients may present with fever or hypothermia. The focus of infection may or may not be apparent.
FBC with differential: often reveals leukocytosis with neutrophilia. [12] Cultures may grow causative organism.
Anaphylaxis
Presents acutely with facial and neck swelling, difficult breathing and wheezing, and often with rash. [13]
Anaphylaxis is a clinical diagnosis and the history is critical.
Drug adverse effect
Variable presentation, depending on the specific offending drug.
Trial withdrawal of offending drug: blood pressure improves on variable timescale, depending on the drug pharmacokinetics.Volume resuscitation may be necessary until the drug is no longer causing hypotension.
Autonomic insufficiency
Hypotension and tachycardia occur consistently with standing. Occasionally, the heart rate may not increase as blood pressure falls.
There is no response to volume resuscitation.

Volume depletion in children

Dehydration
Total body water is depleted, without equivalent reduction in solutes. Patients with pure dehydration usually have relatively fewer signs of intravascular depletion and relatively more signs of intracellular fluid losses (e.g., decreased skin turgor, dry mucous membranes, sunken eyes).
Dehydration is nearly always accompanied by some degree of volume depletion, and test abnormalities overlap significantly with those of volume depletion. Despite significant overlap, the distinction is important in directing therapies and monitoring for complications.In isolated dehydration, serum sodium is high.
Acute glomerulonephritis
Hypertension is usually present.Clinical indicators of fluid retention are present despite decreased urine output.Cola-coloured urine is classically described in acute glomerulonephritis.
Urine sediment has blood, casts, proteinuria, and other abnormalities.Urea and serum creatinine both elevated.
Adrenal insufficiency
Onset of symptoms is generally extremely gradual.Deficiencies of ≥1 of the 3 groups of adrenal steroid hormones can co-exist and in many cases are similar to findings of volume depletion (i.e., fatigue, vomiting, hypotension).In cases of adrenal androgen deficiency, hyperpigmentation may be notable on mucous membranes, extensor surfaces, and palms.
Hyperkalaemia, hyponatraemia, normal anion gap, and metabolic acidosis are classically seen.ECG may show signs of hyperkalaemia.Serum cortisol may be low, but cortisol is always inappropriately low under conditions of stress.
Intussusception or volvulus
Significant abdominal tenderness, bilious emesis, passage of mucus, bloody stool (jelly-like stool), are classically described.A sausage-shaped mass may be palpable and is highly suggestive of intussusceptions.
Plain abdominal x-ray or abdominal CT scan may show obstructive pattern with dilated loops of bowel with air-fluid levels.

Von Willebrand disease

Mild haemophilia A
Bleeding symptoms may be similar, although patients with VWD tend to have more mucosal bleeding symptoms.By family history, VWD is inherited in an autosomal pattern and haemophilia in an X-linked pattern.However, because of the high mutation rate in haemophilia A and because of variable expressivity in VWD, a positive family history may be absent in both.
Patients with haemophilia A have decreased factor VIII, but normal VWF antigen and activity. For VWD all 3 are decreased. Special binding studies or DNA analysis is required to distinguish type 2N VWD from hemophilia A.
Inherited platelet function disorder
Both platelet function disorders and VWD have predominant mucosal bleeding symptoms.Rare severe platelet function disorders such as Glanzmann's thrombasthenia and Bernard-Soulier syndrome are autosomal recessive in inheritance, but most disorders are autosomal dominant.
Platelet aggregometry is abnormal in inherited platelet disorders and normal in VWD.In non-type 2B VWD there may be decreased sensitivity to ristocetin induced platelet agglutination, but this is less sensitive for the diagnosis of VWD than the ristocetin cofactor assay.

Waldenstrom's macroglobulinaemia

Multiple myeloma (MM)
Bone pain related to lytic bone lesions is frequent in MM (bone lesions generally absent in WM).Hyperviscosity syndrome is uncommon in MM (whereas common in WM).Splenomegaly and hepatomegaly are uncommon in MM (whereas common in WM).
Bone marrow biopsy reveals infiltrate of plasma cells that are morphologically different from lymphoplasmacytic cells of WM.Imaging by CT frequently reveals lytic bone lesions, which are usually absent in WM.Flow cytometry and immunohistochemistry reveal tumour cell surface markers specific for multiple myeloma (CD5-, CD10-, CD20-, CD138+, sIg-).
Low-grade B-cell lymphoma
No specific signs or symptoms differentiate this condition from WM.
Lymph node excisional biopsy reveals morphological appearance suggestive of follicular lymphoma (i.e., follicles, small lymphocytes: centrocytes and centroblasts).Bone marrow biopsy reveals infiltrate of small lymphocytes that are morphologically different from lymphoplasmacytic cells of WM.Flow cytometry and immunohistochemistry study reveals tumour cell surface markers specific for low-grade B-cell lymphoma (CD5-, CD10+, CD19+, CD20+, CD23-).
CLL
No specific signs or symptoms differentiate this condition from WM.
High-resolution serum protein electrophoresis with immunofixation may or may not reveal IgM monoclonal protein.Flow cytometry and immunohistochemistry study reveals tumour cell surface markers specific for CLL (CD5+, CD19+, CD20 dim, CD23+).
Marginal zone lymphoma (MZL)
No specific signs or symptoms differentiate this condition from WM.
High-resolution serum protein electrophoresis with immunofixation may or may not reveal IgM monoclonal protein.Flow cytometry and immunohistochemistry study reveals tumour cell surface markers specific for MZL (CD5-, CD10-, CD20+, CD23-).
Follicular lymphoma
No specific symptom differentiating this condition from WM.
Lymph node excision biopsy reveals morphological appearance suggestive of follicular lymphoma (follicles, small lymphocytes: centrocytes and centroblasts).High-resolution serum protein electrophoresis with immunofixation only rarely reveals IgM monoclonal protein.Flow cytometry and immunohistochemistry study reveals tumour cell surface markers specific for follicular lymphoma (CD1-, CD10+, CD5-, CD20+, CD23-).
Monoclonal gammopathy of undetermined significance (MGUS)
Absence of symptoms related to hyperviscosity syndrome, no hepatomegaly, no splenomegaly, no lymphadenopathy, no anorexia, no fatigue.
Blood testing shows normal FBC, serum IgM <30 g/L.Bone marrow biopsy shows <10% of lymphoplasmacytic cells.
Primary cold agglutinin disease (CAD)
No symptoms and signs related to lymphoma, such as lymphadenopathy, splenomegaly.
Imaging shows no radiological evidence of lymphoma such as lymphadenopathy or splenomegaly.Blood testing shows evidence of haemolysis. In addition, direct antiglobulin test (DAT) is positive for anti-C3d; cold agglutinin titre is 1:64 or larger.Bone marrow biopsy: no evidence of lymphoma. [23]

Wernicke's encephalopathy

Alcohol intoxication
A high blood alcohol level can confirm alcohol intoxication but does not exclude co-existent Wernicke's encephalopathy, because the clinical symptoms and signs overlap.
Blood alcohol level above 100 mg/dL in alcohol intoxication.
Alcohol withdrawal
Patients with delirium tremens present with tachycardia, hypertension, agitation, diaphoresis, mydriasis, hallucinations, and seizures.
This is a clinical diagnosis; there are no specific differentiating tests.
Viral encephalitis
Patients typically present with any combination of cognitive impairment, altered sensorium, seizures, fever, or focal neurological deficits.
The findings of CSF analysis, which typically shows a pleocytosis and elevated CSF protein.In certain viral encephalitides, abnormal MRI and EEG findings help to distinguish them from Wernicke's encephalopathy.
Miller-Fisher syndrome
Patients typically present with ophthalmoplegia, ataxia, and reduced or absent reflexes.Mental status is rarely affected in this condition unless complications of respiratory failure or autonomic insufficiency ensue.It is usually preceded by a viral illness.
Anti-GQ1b or -GT1b antibodies are positive in serum, and CSF analysis shows cyto-albuminological dissociation. Nerve conduction studies may show evidence of axonal loss and prolonged F-waves.
Bickerstaff brainstem encephalitis
Patients typically present with diplopia, ataxia, and altered sensorium.
MRI shows high-intensity T2 abnormalities in the brainstem, cerebellum, and thalamus. Anti-GQ1b antibodies are positive in serum. CSF shows elevated protein and a lymphocytic pleocytosis.
Top-of-the-basilar syndrome (paramedian thalamic infarction) or deep cerebral venous thromboses
Patients present with the acute onset of neurological deficits that are typically maximal at onset. The symptoms and signs can mimic those of Wernicke's encephalopathy.
MRI with diffusion accompanied by angiographic evidence of vascular occlusion in a person with vascular risk factors helps to distinguish this from Wernicke's encephalopathy.
Primary CNS lymphoma
In some patients, primary CNS lymphoma has a predilection to spread along periventricular pathways, and its clinical manifestations may mimic those of Wernicke's encephalopathy.
CSF may show positive cytology, flow cytometry, or positive EBV viral PCR. The typical lesions of Wernicke's encephalopathy are symmetric; CNS lymphoma is typically asymmetric with accompanying necrosis.
Toxic encephalopathies
Unless there is a witness to the intoxication, or the patient is known to have access to offending medications or toxins, the presenting symptoms and signs are difficult to distinguish from those of Wernicke's encephalopathy.Offending drugs and toxins include phenytoin, aspirin, carbamazepine, phenobarbital, benzodiazepines, methyl bromide, methanol, ethylene glycol.
A urine drug and volatile toxicology screen should be done in all patients presenting with altered sensorium in whom a clear aetiology is not identified after initial evaluation.
Metabolic encephalopathies
Hepatic and uraemic encephalopathies can cause varying degrees of cognitive dysfunction.
A comprehensive metabolic panel, blood-gas analyses, and serum ammonia can help to distinguish these from Wernicke's encephalopathy.

West Nile virus

HSV encephalitis
No differentiating signs and symptoms.
CSF: PCR detects HSV DNA.MRI or CT (less sensitive): show focal temporal lobe abnormalities.EEG: periodic lateralising epileptiform discharges. [42] [43]
St. Louis encephalitis
No differentiating signs and symptoms.
One of the following: 4-fold increase in the virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample. [44] [45]The plaque-reduction neutralisation test (PRNT) can delineate WNV from other zoonoform viral infections that look similar: for example, St. Louis encephalitis.
Eastern equine encephalitis
No differentiating signs and symptoms.
One of the following: 4-fold increase in the antivirus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample. [45]
Western equine encephalitis
No differentiating signs and symptoms.
One of following: 4-fold increase in the antivirus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample. [45]
Bacterial meningitis
No differentiating signs and symptoms.
CSF: high protein, low glucose, CSF Gram stain positive for specific organisms. [46]
Cryptococcal meningitis
Always suspected in people with compromised immune systems (e.g., AIDS, lymphoma).
Detection of CSF cryptococcal antigens in serum or CSF.Cryptococcus neoformans cultured in serum or CSF.India ink stain of CSF detects the organism. [47]
Tuberculous meningitis
No clear differentiating signs and symptoms.
Detection of acid-fast bacilli in CSF using PCR.CT/MRI: can show cerebral tuberculomas or basilar arachnoiditis. [48]
Guillain-Barre syndrome
Typically presents 1 to 8 weeks following acute viral infection.There is no fever or leukocytosis.Ascending symmetrical weakness.No bowel or bladder dysfunction.No concurrent encephalopathy.
Diagnosis usually clinical. [49]CSF: shows elevated protein, no elevated cell count.
Lyme disease
History of tick bite.More chronic course and gradual onset.Erythema chronicum migrans.Lyme arthritis.Chronic radicular paraesthesias.
Positive serum antibody titre for Borrelia burgdorferi: total Lyme titre or positive IgG and IgM.Western blot (IgM/IgG): to confirm positive titres. [50] [51]
Rocky Mountain spotted fever
Characteristic rash appears 2 to 6 days after fever onset.Initially maculopapular eruption that begins on wrists and ankles and spreads to trunk and extremities, involving palms and soles. Later becomes petechial in appearance. [52]
Serology positive for Rickettsia rickettsii. [53]
Legionnaire's disease
Respiratory symptoms and signs, such as cough, chest tightness, crackles, rhonchi, chest tightness. [54]
Serology: positive for Legionella species. [54]CXR: shows pneumonia. [54]
Brain tumour
Neurological deficit usually focal.Symptom onset more gradual.
CT/MRI: shows mass. [55]
Brain abscess
Neurological deficit usually focal.Symptom onset more gradual.
CT/MRI: shows abscess. [56]
CVA
Neurological deficit usually focal.Progression of signs/symptoms occurs over a few hours, not days or weeks.
CT/MRI: shows infarction and/or haemorrhage. [57]
Sub-acute bacterial endocarditis
Cardiac murmur and signs of CHF present.Characteristic but less common features include splinter haemorrhages, Osler's nodes, Janeway lesions, and Roth's spots.
Bacterial blood cultures: positive.Echocardiogram: shows vegetations. [58] [59]
Dengue fever
Biphasic fever and biphasic rash (transient generalised macular rash followed by a second morbilliform, maculopapular rash).Bone pain.
Detection of virus in serum, immunoglobulins (IgM and IgG), or both by enzyme-linked immunosorbent assay (ELISA) antibody capture, monoclonal antibody, or haemagglutination.

Whipple's disease

Seronegative rheumatoid arthritis
Articular pain in Whipple's disease resembles rheumatoid arthritis. Isolated articular symptoms in patients with Whipple's disease cannot be distinguished clinically from seronegative rheumatoid arthritis.
Synovial membrane samples of patients with seronegative rheumatoid arthritis show inflammatory indices, which include thickening of the lining cell layer and a dense infiltrate of mononuclear cells. However, histology of duodenal or synovial biopsies of patients with seronegative rheumatoid arthritis does not show periodic acid-Schiff (PAS)-positive cells.
Sarcoidosis
Lymphadenopathy of Whipple's disease resembles sarcoidosis.However, in contrast to patients with Whipple's disease, most people with sarcoidosis have lung involvement. Common lung symptoms are dry coughing, trouble breathing or pain with breathing, wheezing, chest pain, tightness, or discomfort, and, only rarely, coughing up blood.
Histology of lymph node specimens of patients with sarcoidosis shows non-caseating granulomas with only mild necrosis and no PAS-positive cells.
Coeliac disease
Gastrointestinal (GI) symptoms of coeliac disease and Whipple's disease are similar.However, the intestinal symptoms of coeliac disease are ameliorated with a gluten-free diet. Coeliac disease is often accompanied by the skin disorder dermatitis herpetiformis (Duhring's disease).
Positive serology for antitransglutaminase antibodies has a high sensitivity and specificity.Small-bowel biopsies show increased intraepithelial lymphocytes (Marsh's classification), flattening and blunting of villi, crypt hyperplasia, and lymphocyte infiltration but no PAS-positive macrophages.
Tropical sprue
GI symptoms of tropical sprue and Whipple's disease are clinically indistinguishable.
Histology of duodenum reveals flattened villi, inflammation of the lining, and inflammatory cell infiltrates but no PAS-positive macrophages.
Mycobacterium avium-intracellulare enteropathy
GI symptoms of M avium-intracellulare (MAI) enteropathy and Whipple's disease are similar. However, MAI infection usually first presents as a persistent cough and almost exclusively affects patients with AIDS or other severely immunosuppressed patients.
Duodenal biopsies from M avium-positive duodenal biopsies are also PAS-positive but, contrary to Whipple's disease specimens, they also stain positive with Ziehl-Neelsen.

Wilms' tumour

Neuroblastoma
May also have failure to thrive, skin metastasis, exophthalmos, or periorbital ecchymoses. [115] [34] [116]
Urine catecholamines are elevated. [115]FBC showing anaemia, neutropenia, or thrombocytopenia may suggest bone marrow infiltration in advanced stage IV neuroblastoma. [117]Cytogenetics shows MYCN gene amplification. [118]Neuroblastoma is heterogeneous in appearance on abdominal ultrasound and typically shows calcifications. Rarely shows tumour extension into the lumen of the renal vein and inferior vena cava. [115]Meta-iodobenzylguanidine (MIBG) scintigraphy usually shows MIBG accumulation. [119]
Clear cell sarcoma of the kidney (CCSK)
More common in males. [120]Does not present as bilateral disease.
Doppler ultrasound of abdomen followed by CT or MRI, usually reveals unicentric renal mass originating from renal medulla and involving the entire kidney.Histology is diagnostic: mucopolysaccharide matrix which gives the classic 'clear' appearance, fibrovascular septa, and small cord cells. [121]Bone scan and bilateral bone marrow biopsies may show bone metastases. [121]
Renal cell carcinoma
Patients are usually older at presentation. [122]More common in males. [122]Higher incidence of metastasis at diagnosis (50%).May be associated with Von Hippel-Lindau syndrome. [123]
Histologically, tumour cells form papillae, tubules, or nests. Tumour cells may appear 'clear' due to accumulation of lipids and glycogen. Surrounding parenchyma may form a pseudocapsule due to compression.
Malignant rhabdoid tumour of the kidney (RTK)
Age at presentation is <2 years of age and more common in males. [124]High incidence of metastasis at diagnosis (50%). [124] Metastatic disease may cause bone pain and headaches.Neurological deficits secondary to metastatic disease (10% to 15% of RTK patients develop CNS lesions). [10] [124]
Cytogenetics shows identification of hSNF5/INI1 gene mutation in tumour tissue. [125]MRI of brain identifies brain metastasis. [103]
Polycystic kidney disease (PKD)
Autosomal-recessive form can present with renal failure in early infancy. [126]Autosomal-dominant form usually presents in adulthood and may present with anuria or renal failure. [126]Hypertension is more common.
Kidneys are generally enlarged and demonstrate multiple irregular cysts on ultrasound.Extrarenal cysts (e.g., liver, pancreas, and spleen) help to confirm diagnosis. [126]
Phaeochromocytoma
Occurs in older children aged 6 to 14 years. [127]Other symptoms may include palpitations, diaphoresis, and nervousness or anxiety.Paroxysmal hypertension, tachycardia, and tremor may also be present.
Urine and serum catecholamines are elevated. [127]Ultrasonography detects larger tumours easily. To better define the location and extent, a contrast CT or MRI should be obtained.Accumulate MIBG avidly; therefore, MIBG scintigraphy is used for tumour surveillance, and to identify extra-adrenal phaeochromocytomas. [127]
Burkitt's lymphoma
More common in males and mean age of presentation is 7 years.Ascites, generalised lymphadenopathy, pancytopenia, and tumour lysis syndrome present.
CT scan usually reveals a lobulated heterogenous mass with areas of necrosis. Tumour may involve adjacent bowel and mesentery. [128]

Wilms’ tumor all stages

Neuroblastoma
May also have failure to thrive, skin metastasis, exophthalmos, or periorbital ecchymoses. [115] [34] [116]
Urine catecholamines are elevated. [115]FBC showing anaemia, neutropenia, or thrombocytopenia may suggest bone marrow infiltration in advanced stage IV neuroblastoma. [117]Cytogenetics shows MYCN gene amplification. [118]Neuroblastoma is heterogeneous in appearance on abdominal ultrasound and typically shows calcifications. Rarely shows tumour extension into the lumen of the renal vein and inferior vena cava. [115]Meta-iodobenzylguanidine (MIBG) scintigraphy usually shows MIBG accumulation. [119]
Clear cell sarcoma of the kidney (CCSK)
More common in males. [120]Does not present as bilateral disease.
Doppler ultrasound of abdomen followed by CT or MRI, usually reveals unicentric renal mass originating from renal medulla and involving the entire kidney.Histology is diagnostic: mucopolysaccharide matrix which gives the classic 'clear' appearance, fibrovascular septa, and small cord cells. [121]Bone scan and bilateral bone marrow biopsies may show bone metastases. [121]
Renal cell carcinoma
Patients are usually older at presentation. [122]More common in males. [122]Higher incidence of metastasis at diagnosis (50%).May be associated with Von Hippel-Lindau syndrome. [123]
Histologically, tumour cells form papillae, tubules, or nests. Tumour cells may appear 'clear' due to accumulation of lipids and glycogen. Surrounding parenchyma may form a pseudocapsule due to compression.
Malignant rhabdoid tumour of the kidney (RTK)
Age at presentation is <2 years of age and more common in males. [124]High incidence of metastasis at diagnosis (50%). [124] Metastatic disease may cause bone pain and headaches.Neurological deficits secondary to metastatic disease (10% to 15% of RTK patients develop CNS lesions). [10] [124]
Cytogenetics shows identification of hSNF5/INI1 gene mutation in tumour tissue. [125]MRI of brain identifies brain metastasis. [103]
Polycystic kidney disease (PKD)
Autosomal-recessive form can present with renal failure in early infancy. [126]Autosomal-dominant form usually presents in adulthood and may present with anuria or renal failure. [126]Hypertension is more common.
Kidneys are generally enlarged and demonstrate multiple irregular cysts on ultrasound.Extrarenal cysts (e.g., liver, pancreas, and spleen) help to confirm diagnosis. [126]
Phaeochromocytoma
Occurs in older children aged 6 to 14 years. [127]Other symptoms may include palpitations, diaphoresis, and nervousness or anxiety.Paroxysmal hypertension, tachycardia, and tremor may also be present.
Urine and serum catecholamines are elevated. [127]Ultrasonography detects larger tumours easily. To better define the location and extent, a contrast CT or MRI should be obtained.Accumulate MIBG avidly; therefore, MIBG scintigraphy is used for tumour surveillance, and to identify extra-adrenal phaeochromocytomas. [127]
Burkitt's lymphoma
More common in males and mean age of presentation is 7 years.Ascites, generalised lymphadenopathy, pancytopenia, and tumour lysis syndrome present.
CT scan usually reveals a lobulated heterogenous mass with areas of necrosis. Tumour may involve adjacent bowel and mesentery. [128]

Wilms’ tumor relapse

Neuroblastoma
May also have failure to thrive, skin metastasis, exophthalmos, or periorbital ecchymoses. [115] [34] [116]
Urine catecholamines are elevated. [115]FBC showing anaemia, neutropenia, or thrombocytopenia may suggest bone marrow infiltration in advanced stage IV neuroblastoma. [117]Cytogenetics shows MYCN gene amplification. [118]Neuroblastoma is heterogeneous in appearance on abdominal ultrasound and typically shows calcifications. Rarely shows tumour extension into the lumen of the renal vein and inferior vena cava. [115]Meta-iodobenzylguanidine (MIBG) scintigraphy usually shows MIBG accumulation. [119]
Clear cell sarcoma of the kidney (CCSK)
More common in males. [120]Does not present as bilateral disease.
Doppler ultrasound of abdomen followed by CT or MRI, usually reveals unicentric renal mass originating from renal medulla and involving the entire kidney.Histology is diagnostic: mucopolysaccharide matrix which gives the classic 'clear' appearance, fibrovascular septa, and small cord cells. [121]Bone scan and bilateral bone marrow biopsies may show bone metastases. [121]
Renal cell carcinoma
Patients are usually older at presentation. [122]More common in males. [122]Higher incidence of metastasis at diagnosis (50%).May be associated with Von Hippel-Lindau syndrome. [123]
Histologically, tumour cells form papillae, tubules, or nests. Tumour cells may appear 'clear' due to accumulation of lipids and glycogen. Surrounding parenchyma may form a pseudocapsule due to compression.
Malignant rhabdoid tumour of the kidney (RTK)
Age at presentation is <2 years of age and more common in males. [124]High incidence of metastasis at diagnosis (50%). [124] Metastatic disease may cause bone pain and headaches.Neurological deficits secondary to metastatic disease (10% to 15% of RTK patients develop CNS lesions). [10] [124]
Cytogenetics shows identification of hSNF5/INI1 gene mutation in tumour tissue. [125]MRI of brain identifies brain metastasis. [103]
Polycystic kidney disease (PKD)
Autosomal-recessive form can present with renal failure in early infancy. [126]Autosomal-dominant form usually presents in adulthood and may present with anuria or renal failure. [126]Hypertension is more common.
Kidneys are generally enlarged and demonstrate multiple irregular cysts on ultrasound.Extrarenal cysts (e.g., liver, pancreas, and spleen) help to confirm diagnosis. [126]
Phaeochromocytoma
Occurs in older children aged 6 to 14 years. [127]Other symptoms may include palpitations, diaphoresis, and nervousness or anxiety.Paroxysmal hypertension, tachycardia, and tremor may also be present.
Urine and serum catecholamines are elevated. [127]Ultrasonography detects larger tumours easily. To better define the location and extent, a contrast CT or MRI should be obtained.Accumulate MIBG avidly; therefore, MIBG scintigraphy is used for tumour surveillance, and to identify extra-adrenal phaeochromocytomas. [127]
Burkitt's lymphoma
More common in males and mean age of presentation is 7 years.Ascites, generalised lymphadenopathy, pancytopenia, and tumour lysis syndrome present.
CT scan usually reveals a lobulated heterogenous mass with areas of necrosis. Tumour may involve adjacent bowel and mesentery. [128]

Wilson's disease

Viral hepatitis B
Patients with viral hepatitis may have a history of a febrile illness or blood transfusion, but otherwise the symptoms and signs may be identical.
Hepatitis B antigen positive.
Viral hepatitis C
Patients with viral hepatitis may have a history of a febrile illness or blood transfusion, but otherwise the symptoms and signs may be identical.
Hepatitis C antibody positive.
Haemochromatosis
Patients with haemochromatosis may present with other features such as diabetes, skin pigmentation, arthritis, impotence in males, and cardiac enlargement with or without symptoms and signs of heart failure.
Iron parameters and liver biopsy are diagnostic.
Alpha-1 antitrypsin deficiency
Patients with alpha-1 antitrypsin deficiency may have chronic lung disease such as emphysema occurring earlier than expected (in the 40- to 50-year-old age group) as well as liver disease.
Tests show that enzyme is deficient.
Auto-immune hepatitis
Patients may have other associated auto-immune conditions and will respond to steroid therapy. However, Wilson's disease should be excluded before this diagnosis is assumed.
Patients may have a positive auto-antibody screen including ANA, primarily in a homogenous pattern, anti-smooth muscle antibody, anti-liver-kidney microsomal antibody, and others.
Steatohepatitis
Patients with steatohepatitis tend to be obese with clinical features of hepatitis. Wilson's disease should be excluded before this diagnosis is assumed.
Fatty liver and inflammation on biopsy.
Alcoholic cirrhosis
Patients may have a history and signs of alcohol excess. Wilson's disease should be excluded before this diagnosis is assumed, even if the patient drinks.
None.
Haemolytic anaemia
If hepatic bouts are severe in Wilson's disease then haemolysis may occur. Haemolysis in the presence of liver disease in a person aged <40 years should prompt testing for Wilson's disease.
Tests for alternative causes of haemolytic anaemia, including Coombs antibody, haemoglobin electrophoresis for HbS, and auto-antibody screening for auto-immune diseases, are used to determine the diagnosis.
Essential tremor
Tremor with no other neurological symptoms of a movement disorder. May have positive family history.Wilson's disease should be excluded before you make this diagnosis especially in all patients aged <40 years and in many aged <50 years.
None.
Parkinson's disease
Parkinson's disease usually occurs in older people (>50 years), but the movement disorders are often identical. The diagnosis of Parkinson's disease is made on history and neurological examination.
None.
Psychiatric disease
Psychiatric disease unrelated to Wilson's disease will not be accompanied by features of Wilson's disease. Wilson's disease patients with primary psychiatric disease are more likely to have early childhood problems, and these patients almost always have Kayser-Fleischer rings.
None.

Wiskott-Aldrich syndrome

Idiopathic thrombocytopenia (ITP)
Unlike WAS, ITP is not present from birth and is not familial. Clinical features can be very similar, as eczema is frequent in children and not all WAS patients have a significant infectious history. The existence of other affected family members suggests WAS.
Platelet size below normal range for WAS.Evidence of autoimmune basis for thrombocytopenia is not a discriminator, as this can be present in WAS as well.
Autoimmune lymphoproliferative syndrome (ALPS)
ALPS may present with autoimmune thrombocytopenia. ALPS is usually associated with a history, or presence, of generalised lymphadenopathy. Lymph node enlargement in ALPS is generally much more striking and greater than that seen in WAS.
Platelet size below normal range for WAS.Double negative T-cells are raised in ALPS and normal in WAS. These double negative cells are TCR alpha-beta+CD3+CD4-CD8- and assays are available only at specialist centres.

Wrinkles

Cutis laxa
Rare, inherited, or acquired connective tissue disorder characterised by degenerative changes in the elastic fibres resulting in loose, pendulous skin.Skin is sagging, redundant, and stretchable, with reduced elastic recoil.Internal organs are frequently involved. Pulmonary diseases such as pulmonary emphysema, cor pulmonale, and right-sided heart failure are often seen. Cardiovascular abnormalities include aortic aneurysm and pulmonary artery multiple branch stenosis.
Clinical differentiation is usually sufficient.Cultured cutis laxa dermal fibroblasts: increased elastolytic activity compared with healthy skin.Skin biopsy: changes in the quantity or morphology of elastin with characteristic fragmentation or loss of elastic fibres and possible abnormal cross-linking of elastin.
Werner's syndrome (progeria or pangeria)
Characteristic clinical signs include short stature (<1.60 m), thin skin, muscle atrophy, wrinkling of the skin and ageing of the face, a scleroderma-like appearance, loss of subcutaneous fat, loss of hair, and nail dystrophy.Cataracts occur between 20 to 40 years of age. Osteoporosis, diabetes mellitus, neoplasias, hyperthyreosis, pituitary dysfunction, arteriosclerosis, soft-tissue calcification, hypogonadism or agonadism, and premature menopause are the most common features of the disease.
Biopsy: histological examination of the skin and subcutaneous tissue reveals thinning of the epidermis, loss of rete ridges, dermal fibrosis, and replacement of the subcutaneous fat with newly synthesised hyalinised collagen.
Xeroderma pigmentosum
Rare autosomal disorder characterised by photosensitivity, pigmentary changes, premature skin ageing, and malignant tumour development due to a cellular hypersensitivity to UV radiation. [44]
Biopsy: initial histological findings include hyperkeratosis and increased melanin pigment in the basal cell layer, elongation and atrophy of the rete ridges, and chronic inflammatory infiltrate in the upper dermis. Atrophy, hyperkeratosis, hyperpigmentation, and telangiectasias are more marked in the later stages. Architectural disorder and atypia are noted at the epidermis, and the dermis may be elastotic.

Wrist fractures

Wrist strain
No deformity.
No evidence of fracture on x-rays.
Ligamentous carpal injury
Most common injury is scapholunate ligament tear with widening of the scapholunate interval.Wrist pain with no signs of a fracture.Pain with palpation on dorsum of wrist at the scapholunate interval.Positive Watson shift test.
No evidence of fracture on radiographs (radial/ulnar deviation and a clenched fist view). Images of the contralateral wrist can be performed for comparison.
Triangular fibrocartilage complex (TFCC) tear
Ulnar-sided wrist pain.Pain with ulnar deviation, more so than radial.Pain with manipulation of distal ulna dorsal/volar.
Very difficult to assess acutely. MRI arthrogram of the wrist is the only way to assess with imaging. Other option would be wrist arthroscopy.

Yellow fever

Dengue haemorrhagic fever
Less likely to present with biphasic illness and more likely to have a rash and adenopathy.
Serological testing confirms diagnosis, but treatment for both diseases is identical (i.e., supportive).
Malaria
Jaundice is common, but haemorrhagic complications are rare. Occasionally, periodic fever is present, but there is no true biphasic illness.
Detection of Plasmodium parasites in thick or thin smears.
Leptospirosis
More prolonged, less toxic disease. Renal failure may occur with a generally mild transaminitis.Severe icterohaemorrhagic leptospirosis (Weil's disease) is difficult to differentiate from yellow fever.
Transaminase levels only mildly elevated.Detection of Leptospira in blood and urine.Response to treatment with antibiotics.
Acute hepatitis
Haemorrhage is rare and occurs late due to hepatic failure.
Hepatitis serologies reveal diagnosis in icteric patients.
Louse-borne relapsing fever
Relapsing disease (in contrast to biphasic disease of yellow fever), which does not recur after the toxic phase.Exposure history differs from that of yellow fever, with epidemic transmission associated with poor living conditions. There is some overlapping, but more restricted, geographical distribution.Renal disease, if present, occurs late and rash is more common.
Response to antibiotics within 24 hours.Confirmation of diagnosis is by a blood smear or serological tests.
Haemorrhagic fevers
Lead to haemorrhagic manifestations, but with less hepatorenal disease than in yellow fever. Jaundice, if present, is rare.
Serological testing confirms diagnosis, but treatment for both diseases is identical (i.e., supportive).

Yersinia infection

Gram-negative sepsis
Symptoms and signs may be similar. Absence of painful buboes in gram-negative sepsis. Secondary septicaemic plague after pneumonic plague is associated with haemoptysis and pleuritic chest pain.
Blood cultures positive for gram-negative bacilli other than Yersinia pestis.
Bacterial pneumonia
Less abrupt onset. Pneumonic plague may cause outbreaks but is now thought to be less contagious than was previously believed. [4] [29]
Sputum or blood culture positive for respiratory pathogens other than Y pestis.
Cat scratch disease
Indolent course without significant systemic features.
Positive serology for Bartonella henselae.
Bacterial lymphadenitis
Lymphadenitis due to streptococci or staphylococci may be associated with lymphangitis or cellulitis. Lymph nodes are more likely to be fluctuant.
Blood cultures or other clinical samples positive for Staphylococcus aureus or streptococcal species.
Mycobacterial infection
Clinical course is indolent. Lymphadenitis tends to be non-tender.
Positive cultures for Mycobacterium species.
Tularaemia
Glandular, typhoidal, and pneumonic presentations may be difficult to distinguish clinically from plague.The 2 conditions co-exist in many endemic areas worldwide.
Positive cultures for Francisella tularensis (laboratory is informed if tularaemia suspected).Positive serology for F tularensis.
Rocky Mountain spotted fever and other ricketssial infections
A more indolent course is typical with less systemic toxicity. Headache is often a prominent feature. Generalised rash is frequent, which may be petechial or maculopapular.
Rickettsial infection may be confirmed serologically.
Infectious diarrhoea (yersiniosis)
Differential diagnosis is broad, as various bacteria, parasites, and viruses cause diarrhoea.
Presence of specific infectious agent on stool or serological testing.
Acute appendicitis (yersiniosis)
Absence of diarrhoea and/or bloody stools. Usually right lower quadrant tenderness.
Diagnosis is clinical.

Zinc deficiency

Hypothyroidism
May be clinically difficult to differentiate.Headaches, cold intolerance, hearing impairment, muscle cramps, modest weight gain, dry skin, eyelid oedema, thick tongue, facial oedema.
Serum TSH: elevated TSH level.
Depression
May be clinically difficult to differentiate.Hx of depressed mood, anhedonia, libido changes, sleep disturbance, psychomotor problems, excessive guilt, poor concentration, suicidal ideation.
Clinical diagnosis.Serum or plasma zinc levels: normal.
Iron deficiency
May co-exist with cases of zinc deficiency and be difficult to differentiate clinically.
FBC with peripheral smear: microcytic anaemia; pale red cells with anisopoikilocytosis (variation in size and shape) and pencil cells.Serum iron: low.TIBC (total iron-binding capacity): increased.Transferrin saturation: <16%.Serum ferritin: low.
Vitamin B12 deficiency
May co-exist with cases of zinc deficiency and be difficult to differentiate clinically.
FBC with peripheral smear: macrocytic anaemia; leukopenia or thrombocytopenia (severe disease); hypersegmented polymorphonucleated cells and megalocytes. May have normal haematological parameters in mild disease.Serum vitamin B12 level: <148 picomols/L (200 picograms/mL).
Folate deficiency
May co-exist with cases of zinc deficiency and be difficult to differentiate clinically.
FBC with peripheral smear: macrocytic anaemia; leukopenia or thrombocytopenia (severe disease); hypersegmented polymorphonucleated cells and megalocytes. May have normal haematological parameters in mild disease.Serum folate level: <7 nanomols/L (3 nanograms/mL)
Vitamin D deficiency
May co-exist with cases of zinc deficiency and be difficult to differentiate clinically.
Serum 25 dihydroxyvitamin D level: low (<37.4 nanomols/L [15 nanograms/mL]).
Vitamin A deficiency
May co-exist with cases of zinc deficiency and be difficult to differentiate clinically.
Serum vitamin A level: low.

Zollinger-Ellison syndrome

Atrophic gastritis
Difficult to differentiate clinically.
Gastric secretory analysis will show decreased acid secretion.
Peptic ulcer disease from Helicobacter pylori infection
Difficult to differentiate clinically.
Increased fasting serum gastrin in the presence of achlorhydria (due to H pylori). [16]The exaggerated serum gastrin level response to food stops after H pylori eradication.
Idiopathic gastric hypersecretion
Difficult to differentiate clinically.
Post-prandial hypersecretion of acid without presence of gastrin-secreting tumour.Normal gastrin levels.
Antral G cell hyperfunction and hyperplasia
Difficult to differentiate clinically.
Secretin infusion test is positive in Zollinger-Ellison syndrome (ZES) (gastrin increase >96.2 picomols/L [200 picograms/mL] above basal) but negative in antral G cell hyperfunction.This condition is differentiated from ZES. The presence of a gastrin-releasing tumour in ZES would give results of serum gastrin elevated to 96.2 picomols/L (200 picograms/mL) within 15 minutes of secretin infusion and fasting serum gastrin >481 picomols/L (>1000 picograms/mL). Both of these results would not be seen in hyperfunction and hyperplasia.
Chronic renal failure
Fatigue, weakness, dyspnoea, pleuritic pain, restless legs, and pruritus may be differentiating symptoms.Pallor, brown nails, bruising, and oedema may be differentiating signs.
Gastrin levels are not affected by haemodialysis but will return to normal after renal transplant. [17] [18]Elevated serum creatinine and decreased glomerular filtration rate, which are not seen in ZES.
Retained antrum syndrome
Difficult to differentiate clinically.May be a history of prior Billroth I and II resections.
Negative secretin infusion test.
Pernicious anaemia
Common features include tiredness, dyspnoea, paraesthesiae, sore red tongue, diarrhoea, and mild jaundice.
Once patient is given intrinsic factor, and vitamin B12 level is normal, gastrin levels will normalise.Achlorhydria.
Systemic mastocytosis
Urticarial skin lesions may occur.
Biopsies of the gastric or intestinal mucosa may reveal increase in mast cells.
Proton-pump inhibitor (PPI) use
Difficult to differentiate clinically.
PPI use can cause an appropriate fasting hypergastrinaemia. To diagnose ZES in patients on PPI therapy, a fasting serum gastrin level can be repeated 1 week following discontinuation of PPI. Alternatively, basal acid output (BAO) measured on PPI therapy should be low (<10 mEq/hour) whereas BAO measured in patients with ZES must be high to make the diagnosis.